Substituted phenylcyclohexanecarboxamides and their use

ABSTRACT

The present invention relates to substituted phenylcyclohexanecarboxamides of the Formula (I)  
                 
 
     to processes for their preparation and to their use in medicaments, in particular for the prevention and/or treatment of cardiovascular disorders.

[0001] The present invention relates to substitutedphenylcyclohexanecarboxamides, to a process for their preparation and totheir use in medicaments, in particular for the prevention and/ortreatment of cardiovascular disorders, for example for the acute andchronic treatment of ischaemic disorders.

[0002] Adenosine is an endogenic effector with cell-protective activity,in particular under cell-damaging conditions with limited oxygen supply,such as, for example, in the case of ischaemia. Adenosine is a highlyeffective vasodilator. It increases ischaemic “preconditioning” (R.Strasser, A. Vogt, W. Scharper, Z. Kardiologie 85, 1996, 79-89) and canpromote the growth of collateral vessels. It is released under hypoxicconditions, for example in the case of cardiac or peripheral occlusivediseases (W. Makarewicz “Purine and Pyrimidine Metabolism in Man”,Plenum Press New York, 11, 1998, 351-357). Accordingly, adenosineprotects against the effects of disorders caused by ischaemia, forexample by increasing the coronary or peripheral circulation byvasodilation, by inhibiting platelet aggregation and by stimulatingangiogenesis. Compared to systemically administered adenosine, theadenosine-uptake inhibitors have the advantage of selectivity forischaemia. Moreover, systemically administered adenosine has a veryshort half-life. Systemically administered adenosine causes a strongsystemic lowering of the blood pressure, which is undesirable, sincecirculation into the ischaemic regions may be reduced even further(“steal phenomenon”, L. C. Becker, Circulation 57, 1978, 1103-1110). Theadenosine-uptake inhibitor increases the effect of the adenosine whichis formed locally owing to the ischaemia and thus only dilates thevessels in the ischaemic regions. Accordingly, orally or intravenouslyadministered adenosine-uptake inhibitors can be used for preventingand/or treating ischaemic disorders.

[0003] Furthermore, there have been various indications of aneuroprotective, anticonvulsive, analgesic and sleep-inducing potentialof adenosine-uptake inhibitors, since they increase the intrinsiceffects of adenosine by inhibiting its cellulare re-uptake (K. A.Rudolphi et al., Cerebrovascular and Brain Metabolism Reviews 4, 1992,364-369; T. F. Murray et al., Drug Dev. Res. 28, 1993, 410-415; T.Porkka-Heiskanen et al., Science 276, 1997, 1265-1268; ‘Adenosine in theNervous System’, Ed.: Trevor Stone, Academic Press Ltd. 1991, 217-227;M. P. DeNinno, Annual Reports in Medicinal Chemistry 33, 1998, 111-120).

[0004] It is an object of the present invention to provide novelsubstances for preventing and/or treating cardiovascular disorders, thesubstances having improved administration properties.

[0005] The present invention relates to compounds of the formula

[0006] in which

[0007] D represents a radical

[0008] in which

[0009] R² represents hydrogen, halogen, hydroxyl, carboxyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor (C₁-C₆)-alkoxycarbonyl,

[0010] A represents an oxygen atom or a group of the formula N—R⁵ orCH—R⁶,

[0011] in which

[0012] R⁵ represents hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, wherealkyl and cycloalkyl for their part may be substituted up to three timesindependently of one another by hydroxyl or mono- ordi-(C₁-C₆)-alkylamino, represents (C₆-C₁₀)-aryl, 5- to 10-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and S or 5- or 6-membered heterocyclyl having up to threeheteroatoms from the group consisting of N, O and S, where aryl,heteroaryl and heterocyclyl for their part may be substituted up tothree times independently of one another by halogen, hydroxyl, cyano,nitro, tri fluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl or mono- ordi-(C₁-C₆)-alkylamino,

[0013] R⁶ represents hydrogen, (C₁-C₆)-alkoxycarbonyl or carboxyl,

[0014] R¹ represents hydrogen, (C₁-C₆)-alkyl, which for its part may besubstituted by hydroxyl or (C₁-C₄)-alkoxy, represents(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl havingup to two heteroatoms from the group consisting of N, O and S, wherearyl and heteroaryl for their part may be substituted independently ofone another by halogen, or represents a radical of the formula —NR⁷R⁸ or—OR⁹,

[0015] in which

[0016] R⁷ and R⁸ independently of one another represent hydrogen,(C₆-C₁₀)-aryl, adamantyl, (C₁-C₈)-alkyl, whose chain may be interruptedby one or two oxygen atoms and which may be substituted up to threetimes independently of one another by hydroxyl, phenyl, trifluoromethyl,(C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, 5-or 6-membered heterocyclyl having up to three heteroatoms from the groupconsisting of N, O and S or by 5- to 10-membered heteroaryl having up tothree heteroatoms from the group consisting of N, O and S, represent(C₃-C₈)-cycloalkyl, which may be substituted up to three timesindependently of one another by (C₁-C₄)-alkyl, hydroxyl or oxo, orrepresent 5- or 6-membered heterocyclyl having up to two heteroatomsfrom the group consisting of N, O and S, where N is substituted byhydrogen or (C₁-C₄)-alkyl, or

[0017] R⁷ and R⁸ together with the nitrogen atom to which they areattached form a 4- to 7-membered saturated heterocycle which may containup to two further heteroatoms from the group consisting of N, O and Sand which is optionally substituted by hydroxyl, oxo or (C₁-C₆)-alkyl,which for its part may be substituted by hydroxyl, and

[0018] R⁹ represents (C₆-C₁₀)-aryl, adamantyl, (C₁-C₈)-alkyl, whosechain may be interrupted by one or two oxygen atoms and which may besubstituted up to three times independently of one another by hydroxyl,phenyl, trifluoromethyl, (C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, mono- ordi-(C₁-C₆)-alkylamino, 5- or 6-membered heterocyclyl having up to threeheteroatoms from the group consisting of N, O and S or by 5- to10-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S, represents (C₃-C₈)-cycloalkyl, which may besubstituted up to three times independently of one another by(C₁-C₄)-alkyl, hydroxyl or oxo, or represents 5- or 6-memberedheterocyclyl having up to two heteroatoms from the group consisting ofN, O and S, where N is substituted by hydrogen or (C₁-C₄)-alkyl,

[0019] R³ represents (C₁-C₈)-alkyl, whose chain may be interrupted by asulphur or oxygen atom or an S(O) or SO₂ group, represents phenyl,benzyl or 5- or 6-membered heteroaryl having up to two heteroatoms fromthe group consisting of N, O and S, where phenyl, benzyl and heteroarylmay be substituted up to three times independently of one another byhalogen, trifluoromethyl, cyano, nitro, hydroxyl, (C₁-C₆)-alkyl or(C₁-C₆)-alkoxy, and

[0020] R⁴ represents a radical of the formula —C(O)—NR¹⁰R¹¹,

[0021] in which

[0022] R¹⁰ and R¹¹ independently of one another represent hydrogen or(C₁-C₆)-alkyl,

[0023] and their salts, hydrates, hydrates of the salts and solvates.

[0024] Salts of the compounds according to the invention arephysiologically acceptable salts of the substances according to theinvention with mineral acids, carboxylic acids or sulphonic acids.Particular preference is given, for example, to salts of hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acids, acetic acid,propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid,maleic acid or benzoic acid.

[0025] Salts can also be physiologically acceptable metal or ammoniumsalts of the compounds according to the invention. Particularlypreferred are alkali metal salts (for example sodium salts or potassiumsalts), alkaline earth metal salts (for example magnesium salts orcalcium salts), and also ammonium salts, which are derived from ammoiaor organic amines, such as, for example, ethylamine, di- ortriethylamine, di- or triethanolamine, dicyclohexylamine,dimethylaminoethanol, arginine, lysine, ethylenediamine or2-phenylethylamine.

[0026] Depending on the substitution pattern, the compounds according tothe invention can exist in stereoisomeric forms which are either likeimage and mirror image (enantiomers) or which are not like image andmirror image (diastereomers). The invention relates both to theenantiomers or diastereomers and to their respective mixtures. Theracemic forms, like the diastereomers, can be separated in a knownmanner into the stereoisomerically uniform components.

[0027] Moreover, the invention also includes prodrugs of the compoundsaccording to the invention. According to the invention, prodrugs arethose forms of the compounds of the above formula (I) which for theirpart may be biologically active or inactive, but which are convertedunder physiological conditions (for example metabolically orsolvolytically) into the corresponding biologically active form.

[0028] According to the invention, “hydrates” or “solvates” are thoseforms of the compounds of the above formula (I) which, in solid orliquid state, form a molecular compound or a complex by hydration withwater or coordination with solvent molecules. Examples of hydrates aresesquihydrates, monohydrates, dihydrates and trihydrates. Equallysuitable are the hydrates or solvates of salts of the compoundsaccording to the invention.

[0029] Halogen represents fluorine, chlorine, bromine and iodine.Preference is given to chlorine or fluorine.

[0030] (C₁-C₈)-alkyl represents a straight-chain or branched alkylradical having 1 to 8 carbon atoms. Examples which may be mentioned are:methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,n-pentyl, n-hexyl and n-octyl. The corresponding alkyl groups havingfewer carbon atoms, such as, for example (C₁-C₆)-alkyl, (C₁-C₄)-alkyland (C₁-C₃)-alkyl, are derived analogously from this definition. Ingeneral, (C₁-C₃)-alkyl is preferred.

[0031] The meaning of the corresponding component of other, more complexsubstituents, such as, for example, di-alkylamino, mono- ordi-alkylamino is also derived from this definition.

[0032] Mono- or di-(C₁-C₄)-alkylamino represents an amino group havingone or two identical or different straight-chain or branched alkylsubstituents of in each case 1 to 4 carbon atoms. Examples which may bementioned are: methylamino, ethylamino, n-propylamino, isopropyl amino,tert-butyl amino, N,N-dimethylamino, N,N-diethylamino,N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino and N-t-butyl-N-methylamino.

[0033] C₃-C₈)-Cycloalkyl represents a cyclic alkyl radical having 3 to 8carbon atoms. Examples which may be mentioned are: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Thecorresponding cycloalkyl groups having fewer carbon atoms, such as, forexample, (C₃-C₇)-cycloalkyl or (C₃-C₆)-cycloalky, are derivedanalogously from this definition. Preference is given to cyclopropyl,cyclopentyl and cyclohexyl.

[0034] (C₁-C₆)-Alkoxy represents a straight-chain or branched alkoxyradical having 1 to 6 carbon atoms. Examples which may be mentioned:methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,tert-butoxy, n-pentoxy and n-hexoxy. The corresponding alkoxy groupshaving fewer carbon atoms, such as, for example, (C₁-C₄)-alkoxy or(C₁-C₃)-alkoxy, are derived analogously from this definition. Ingeneral, (C₁-C₃)-alkoxy is preferred.

[0035] The meaning of the corresponding component of other, more complexsubstituents, such as, for example, alkoxycarbonyl, which represents analkoxy radical which is attached via a carbonyl group, is also derivedfrom this definition.

[0036] (C₆-C₁₀)-Aryl represents an aromatic radical having 6 to 10carbon atoms. Examples which may be mentioned are: phenyl and naphthyl.

[0037] 5- to 10-membered heteroaryl having up to 3 heteroatoms from thegroup consisting of N, O and S represents a mono- or bicyclicheteroaromatic which is attached via a ring carbon atom of theheteroaromatic, if appropriate also via a ring nitrogen atom of theheteroaromatic. Examples which may be mentioned are: pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, thienyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl, oxdiazolyl, isoxazolyl, benzofuranyl,benzothienyl or benzimidazolyl. The corresponding heterocycles havingfewer heteroatoms, such as, for example, those having up to 2heteroatoms from the group consisting of N, O and S are derivedanalogously from this definition. In general, preference is given to 5-or 6-membered aromatic heterocycles having up to 2 heteroatoms from thegroup consisting of N, O and S, such as, for example, pyridyl,pyrimidyl, pyridazinyl, furyl, imidazolyl and thienyl.

[0038] 5- or 6-membered heterocyclyl having up to 3 heteroatoms from thegroup consisting of N, O and S represents a saturated or partiallyunsaturated heterocycle which is attached via a ring carbon atom or aring nitrogen atom. Examples which may be mentioned are:tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, dihydropyridinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl. Preference isgiven to saturated heterocycles, in particular to piperidinyl,piperazinyl, morpholinyl and pyrrolidinyl.

[0039] The compounds of the formula (I) according to the invention canbe present in at least eight different configurations, the fourdifferent configurations (Ia) to (Id) below being preferred:

[0040] Particular preference is given to the configuration (Id).

[0041] Preference is furthermore given to compounds of the formula (I)according to the invention

[0042] in which

[0043] D represents a radical

[0044] in which

[0045] R² represents hydrogen, halogen, hydroxyl, carboxyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor (C₁-C₆)-alkoxycarbonyl,

[0046] A represents an oxygen atom or a group of the formula N—R⁵ orCH—R⁶,

[0047] in which

[0048] R⁵ represents hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, wherealkyl and cycloalkyl for their part may be substituted up to three timesindependently of one another by hydroxyl or mono- ordi-(C₁-C₆)-alkylamino, represents (C₆-C₁₀)-aryl, 5- to 10-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and S or 5- or 6-membered heterocyclyl having up to threeheteroatoms from the group consisting of N, O and S, where aryl,heteroaryl and heterocyclyl for their part may be substituted up tothree times independently of one another by halogen, hydroxyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl or mono- or di-(C₁-C₆)-alkylamino,

[0049] R⁶ represents hydrogen, (C₁-C₆)-alkoxycarbonyl or carboxyl,

[0050] R¹ represents hydrogen, (C₁-C₆)-alkyl, which for its part may besubstituted by hydroxyl or (C₁-C₄)-alkoxy, represents(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl havingup to two heteroatoms from the group consisting of N, O and S, wherearyl and heteroaryl for their part may be substituted independently ofone another by halogen, or represents a radical of the formula —NR⁷R⁸ or—OR⁹,

[0051] in which

[0052] R⁷ and R⁸ independently of one another represent hydrogen,(C₆-C₁₀)-aryl, adamantyl, (C₁-C₈)-alkyl, whose chain may be interruptedby one or two oxygen atoms and which may be substituted up to threetimes independently of one another by hydroxyl, phenyl, trifluoromethyl,(C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, 5-or 6-membered heterocyclyl having up to three heteroatoms from the groupconsisting of N, O and S or by 5- to 10-membered heteroaryl having up tothree heteroatoms from the group consisting of N, O and S, represent(C₃-C₈)-cycloalkyl, which may be substituted up to three timesindependently of one another by (C₁-C₄)-alkyl, hydroxyl or oxo, orrepresent 5- or 6-membered heterocyclyl having up to two heteroatomsfrom the group consisting of N, O and S, where N is substituted byhydrogen or (C₁-C₄)-alkyl, or

[0053] R⁷ and R⁸ together with the nitrogen atom to which they areattached form a 4- to 7-membered saturated heterocycle which may containup to two further heteroatoms from the group consisting of N, O and Sand which is optionally substituted by hydroxyl, oxo or (C₁-C₆)-alkyl,which for its part may be substituted by hydroxyl, and

[0054] R⁹ represents (C₆-C₁₀)-aryl, adamantyl, (C₁-C₈)-alkyl, whosechain may be interrupted by one or two oxygen atoms and which may besubstituted up to three times independently of one another by hydroxyl,phenyl, trifluoromethyl, (C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, mono- ordi-(C₁-C₆)-alkylamino, 5- or 6-membered heterocyclyl having up to threeheteroatoms from the group consisting of N, O and S or by 5- to10-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S, represents (C₃-C₈)-cycloalkyl, which may besubstituted up to three times independently of one another by(C₁-C₄)-alkyl, hydroxyl or oxo, or represents 5- or 6-memberedheterocyclyl having up to two heteroatoms from the group consisting ofN, O and S, where N is substituted by hydrogen or (C₁-C₄)-alkyl,

[0055] R³ represents (C₁-C₈)-alkyl, whose chain may be interrupted by asulphur atom or an S(O) or SO₂ group, represents phenyl, benzyl or 5- or6-membered heteroaryl having up to two heteroatoms from the groupconsisting of N, O and S, where phenyl, benzyl and heteroaryl may besubstituted up to three times independently of one another by halogen,trifluoromethyl, cyano, nitro, hydroxyl, (C₁-C₆)-alkyl or(C₁-C₆)-alkoxy, and

[0056] R⁴ represents a radical of the formula —C(O)—NR¹⁰R¹¹,

[0057] in which

[0058] R¹⁰ and R¹¹ independently of one another represent hydrogen or(C₁-C₆)-alkyl,

[0059] and their salts, hydrates, hydrates of the salts and solvates.

[0060] Particular preference is given to compounds of the formula (I)according to the invention,

[0061] in which

[0062] D represents a radical

[0063] in which

[0064] R² represents hydrogen, chlorine or fluorine,

[0065] A represents an oxygen atom or a group of the formula N—R⁵,

[0066] in which

[0067] R⁵ represents hydrogen, (C₁-C₆)-alkyl, which for its part may besubstituted up to two times by hydroxyl, represents (C₃-C₇)-cycloalkyl,phenyl or 5- or 6-membered heteroaryl having up to three heteroatomsfrom the group consisting of N, O and S, where phenyl and heteroaryl fortheir part may be substituted up to two times independently of oneanother by halogen, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₄)-alkyl, (C₁-C₄)-alkoxy or di-(C₁-C₄)-alkylamino,

[0068] R¹ represents hydrogen, (C₁-C₆)-alkyl, which for its part may besubstituted by hydroxyl or (C₁-C₄)-alkoxy, represents(C₃-C₇)-cycloalkyl, phenyl, 5- or 6-membered heteroaryl having up to twoheteroatoms from the group consisting of N, O and S, where phenyl andheteroaryl for their part independently of one another may besubstituted by halogen, or represents a radical of the formula —NR⁷R⁸ or—OR⁹,

[0069] in which

[0070] R⁷ and R⁸ independently of one another represent hydrogen,phenyl, adamantyl, (C₁-C₆)-alkyl, whose chain may be interrupted by oneor two oxygen atoms and which may be substituted up to two timesindependently of one another by hydroxyl, phenyl, trifluoromethyl,(C₃-C₆)-cycloalkyl, (C₁-C₄)-alkoxy, mono- or di-(C₁-C₄)-alkylamino, 5-or 6-membered heterocyclyl having up to two heteroatoms from the groupconsisting of N and O or by 5- or 6-membered heteroaryl having up tothree heteroatoms from the group consisting of N, O and S, represents(C₃-C₈)-cycloalkyl, which may be substituted up to two times byhydroxyl, or represent 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N, O and S, where N issubstituted by hydrogen or (C₁-C₄)-alkyl, or

[0071] R⁷ and R⁸ together with the nitrogen atom to which they areattached form a 4- to 7-membered saturated heterocycle which may containup to two further heteroatoms from the group consisting of N, O and Sand which is optionally substituted by hydroxyl, oxo or (C₁-C₆)-alkyl,which for its part may be substituted by hydroxyl, and

[0072] R⁹ represents phenyl, adamantyl, (C₁-C₆)-alkyl, whose chain maybe interrupted by one or two oxygen atoms and which may be substitutedup to two times independently of one another by hydroxyl, phenyl,trifluoromethyl, (C₃-C₆)-cycloalkyl, (C₁-C₃)-alkoxy, mono- ordi-(C₁-C₄)-alkylamino, 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N and O or by 5- or 6-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and S, represents (C₃-C₈)-cycloalkyl, which may be substituted upto two times by hydroxyl, or represents 5- or 6-membered heterocyclylhaving up to two heteroatoms from the group consisting of N, O and S,where N is substituted by hydrogen or (C₁-C₄)-alkyl,

[0073] R³ represents (C₁-C₈)-alkyl, whose chain may be interrupted by asulphur atom or an S(O) or SO₂ group, represents phenyl, benzyl or 5- or6-membered heteroaryl having up to two heteroatoms from the groupconsisting of N, O and S, where phenyl, benzyl and heteroaryl may besubstituted up to two times independently of one another by halogen,trifluoromethyl, cyano, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy or hydroxyl, and

[0074] R⁴ represents a radical of the formula —C(O)—NR¹⁰R¹¹,

[0075] in which

[0076] R¹⁰ and R¹¹ independently of one another represent hydrogen or(C₁-C₆)-alkyl,

[0077] and their salts, hydrates, hydrates of the salts and solvates.

[0078] Very particular preference is given to compounds of the formula(I) according to the invention

[0079] in which

[0080] D represents a radical

[0081] in which

[0082] R² represents hydrogen,

[0083] A represents an oxygen atom or a group of the formula N—R⁵,

[0084] in which

[0085] R⁵ represents hydrogen, (C₁-C₆)-alkyl, which for its part may besubstituted up to two times by hydroxyl, represents (C₃-C₇)-cycloalkyl,phenyl or 5- or 6-membered heteroaryl having up to three heteroatomsfrom the group consisting of N, O and S, where phenyl and heteroaryl fortheir part may be substituted up to two times independently of oneanother by fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy,(C₁-C₃)-alkyl, (C₁-C₃)-alkoxy or di-(C₁-C₃)-alkylamino,

[0086] R¹ represents (C₁-C₄)-alkyl or a radical of the formula —NR⁷R⁸,

[0087] in which

[0088] R⁷ and R⁸ independently of one another represent hydrogen,phenyl, adamantyl, (C₁-C₄)-alkyl, whose chain may be interrupted by oneor two oxygen atoms and which may be substituted up to two timesindependently of one another by hydroxyl, phenyl, trifluoromethyl,(C₃-C₆)-cycloalkyl, (C₁-C₃)-alkoxy, mono- or di-(C₁-C₃)-alkylamino, 5-or 6-membered heterocyclyl having up to two heteroatoms from the groupconsisting of N and O or by 5- or 6-membered heteroaryl having up tothree heteroatoms from the group consisting of N, O and S, represent(C₃-C₈)-cycloalkyl, which may be substituted up to two times byhydroxyl, or represents 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N, O and S, where N issubstituted by hydrogen or (C₁-C₄)-alkyl, or

[0089] R⁷ and R⁸ together with the nitrogen atom to which they areattached form a 4- to 7-membered saturated heterocycle which may containup to two further heteroatoms from the group consisting of N, O and Sand which is optionally substituted by by hydroxyl, oxo or(C₁-C₆)-alkyl, which for its part may be substituted by hydroxyl,

[0090] R³ represents (C₁-C₈)-alkyl, whose chain may be interrupted by asulphur atom or an S(O) or SO₂ group, represents phenyl, benzyl or 5- or6-membered heteroaryl having up to two heteroatoms from the groupconsisting of N, O and S, where phenyl, benzyl and heteroaryl may besubstituted up to two times independently of one another by halogen,trifluoromethyl, cyano, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy or hydroxyl, and

[0091] R⁴ represents a radical of the formula —C(O)—NR¹⁰R¹¹,

[0092] in which

[0093] R¹⁰ and R¹ independently of one another represent hydrogen,methyl or ethyl,

[0094] and their salts, hydrates, hydrates of the salts and solvates.

[0095] Most particular preference is given to compounds of the formula(I),

[0096] in which

[0097] D is a radical

[0098] in which

[0099] R² represents hydrogen,

[0100] A represents an oxygen atom or a group of the formula N—R⁵,

[0101] in which

[0102] R⁵ represents (C₃-C₇)-cycloalkyl, phenyl, which for its part maybe substituted by fluorine, or represents pyridyl,

[0103] R¹ represents methyl or a radical of the formula —NR⁷R⁸,

[0104] in which

[0105] R⁷ and R⁸ independently of one another represent (C₁-C₄)-alkyl,which may be mono- or disubstituted by hydroxyl, or

[0106] R⁷ and R⁸ together with the nitrogen atom to which they areattached form a 5- or 6-membered saturated heterocycle which may containa further heteroatom O or N, where N is substituted by hydrogen or(C₁-C₃)-alkyl, which for its part may be substituted by hydroxyl,

[0107] R³ represents phenyl, which is optionally substituted in thepara-position by fluorine, or represents pyridyl, and

[0108] R⁴ represents a radical of the formula —C(O)—NR¹⁰R¹¹,

[0109] in which

[0110] R¹⁰ and R¹¹ represent hydrogen,

[0111] and their salts, hydrates, hydrates of the salts and solvates.

[0112] Most particular preference is also given to:

[0113](1R,2R)-N-[(1S)-2-amino-1-(4-fluorophenyl)-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(4-fluorophenyl)amino]methyl}phenyl)cyclohexanecarboxamide

[0114](1R,2R)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-(4-{[[(dimethylamino)carbonyl]-(phenyl)amino]methyl}phenyl)cyclohexanecarboxamide

[0115] (1R,2R)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-[4-({cyclopropyl[(dimethylamino)-carbonyl]-amino}methyl)phenyl]cyclohexanecarboxamide

[0116](1R,2R)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-(4-{[[(diethylamino)carbonyl](2-pyridinyl)amino]methyl}phenyl)cyclohexanecarboxamide

[0117]N-{4-[(1R,2R)-2-({[(1S)-2-amino-2-oxo-1-phenylethyl]amino}carbonyl)cyclohexyl]-benzyl}-N-phenyl-4-morpholinecarboxamide

[0118](S)-N-{{(1R,2R)-2-(4-{[{[2-hydroxylethylamino]carbonyl}(phenyl)amino]methyl}-phenyl)cyclohex-1-yl}carbonyl}-phenylglycinamide

[0119](1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}phenyl)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]cyclohexancarboxamide

[0120](1R,2R)-N-[(1S)-2-amino-1-phenyl-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)-amino]carbonyl}(phenyl)amino]methyl}phenyl)cyclohexanecarboxamide

[0121]4-[(1R,2R)-2-({[(1S)-2-amino-1-(4-fluorophenyl)-2-oxoethyl]amino}carbonyl)cyclohexyl]benzyl4-(2-hydroxyethyl)-1-piperazinecarbamate

[0122]4-[(1R,2R)-2-({[(1S)-2-amino-1-phenyl-2-oxoethyl]amino}carbonyl)cyclohexyl]-benzyl-4-(2-hydroxyethyl)-1-piperazinecarbamate

[0123] and their salts, hydrates, hydrates of the salts and solvates.

[0124] Moreover, we have found a process for preparing the compounds ofthe formula (I) according to the invention where

[0125] [A] compounds of the formula (II)

[0126] in which

[0127] D is as defined above,

[0128] T represents (C₁-C₄)-alkyl, preferably methyl or tert-butyl, and

[0129] V represents a suitable leaving group, such as, for example,halogen, mesylate or tosylate, preferably bromine,

[0130] are initially converted by reaction with compounds of the formula(III)

B—H  (III),

[0131] in which

[0132] B represents

[0133] or

[0134] optionally, if R¹ reprsents OR⁹,

[0135] represents

[0136] and

[0137] R¹ and A are each as defined above, where any amino and hydroxylfunctions which may be present are optionally blocked by customary aminoor hydroxyl protective groups,

[0138] and to the compounds of the formula (IV)

[0139] in which B, D and T are each as defined above,

[0140] these reaction mixtures obtained are in a next step convertedwith acids or bases into the corresponding carboxylic acids of theformula (V)

[0141] in which

[0142] R¹, A and D are as defined above,

[0143] which are, if appropriate, activated, in particular by conversioninto a corresponding carboxylic acid derivative, such as a carbonylhalide, a carboxylic anhydride or a carboxylic acid,

[0144] and these compounds are finally reacted in inert solventsaccording to known methods with compounds of the formula (VI) or saltsthereof

[0145] in which

[0146] R³ and R⁴ are as defined above,

[0147] or

[0148] [B] if A represents an oxygen atom or NR⁵,

[0149] compounds of the formula (VII)

[0150] in which

[0151] D, R³ and R⁴ are as defined above

[0152] and

[0153] A represents an oxygen atom or a group of the formula N—R⁵,

[0154] where R⁵ is as defined above,

[0155] if appropriate in the presence of a base,

[0156] are reacted either with compounds of the formula (VIII)

[0157] in which

[0158] R¹ is as defined above and W represents a suitable leaving group,such as, for example, the corresponding symmetric anhydride or ahalogen, preferably chlorine,

[0159] or

[0160] with a phosgene equivalent, such as, for example, disuccinimidylcarbonate, and then with compounds of the formula (IX)

R⁷R⁸NH  (IX),

[0161] in which

[0162] R⁷ and R⁸ are as defined above,

[0163] or

[0164] with an isocyanate of the formula (X)

R⁷NCO  (X),

[0165] in which

[0166] R⁷ is as defined above.

[0167] The compounds of the formula (I) obtained according to processvariant [A] or [B] can, if appropriate, subsequently be converted intothe corresponding salts, for example by reaction with an acid.

[0168] The compounds of the corresponding diastereomeric andenantiomeric forms are prepared correspondingly, either usingenantiomerically or diastereomerically pure starting materials or bysubsequent separation of the racemates formed by customary methods (forexample racemate resolution, chromatography on chiral columns, etc.).

[0169] The process according to the invention is illustrated in anexemplary manner by the equation below:

[0170] If R¹ represents OR⁹, the following synthesis sequence islikewise possible:

[0171] The process according to the invention is generally carried outunder atmospheric pressure. However, it is also possible to carry outthe process under elevated pressure or under reduced pressure (forexample in a range from 0.5 to 5 bar).

[0172] In the context of the invention, customary amino protectivegroups are the amino protective groups used in peptide chemistry.

[0173] These preferably include: benzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl,allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl, cyclohexoxycarbonyl,1,1-dimethylethoxycarbonyl, adamantylcarbonyl, phthaloyl,2,2,2-trichlorethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl,Menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl,2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl,2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene,4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl. A preferredprotective group for primary amines is phthalimide. Preferred protectivegroups for secondary amines are benzyloxycarbonyl andtert-butoxycarbonyl.

[0174] The amino protective groups are removed in a manner known per se,using, for example, hydrogenolytic, acidic or basic conditions,preferably acids, such as, for example, hydrochloric acid ortrifluoroacetic acid, in inert solvents, such as ether, dioxane andmethylene chloride.

[0175] In the context of the definition given above, a customaryhydroxyl protective group is generally a protective group from thegroup: trimethylsilyl, triethylsilyl, triisopropylsilyltert-butyl-dimethylsilyl, tert-butyldiphenylsilyl, di methylhexylsilyl,dimethylthexylsilyl, trimethylsilylethoxycarbonyl, benzyl,triphenylmethyl(trityl), monomethoxytrityl (MMTr), dimethyloxytrityl(DMTr), benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl,2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,tert-butyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl,formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl,2,4-dimethoxybenzyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl,methylthiomethyl, methoxyethoxymethyl,[2-(trimethylsilyl)ethoxy]-methyl, 2-(methylthiomethoxy)ethoxycarbonyl,tetrahydropyranyl, benzoyl, N-succinimide, 4-methylbenzoyl,4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl or 4-methoxybenzoyl.Preference is given to tert-butyl-dimethylsilyl.

[0176] The hydroxyl protective group is removed in a manner known perse, for example using acid, base or by addition of tetrabutylammoniumfluoride.

[0177] Solvents suitable for the process are customary organic solventswhich do not change under the reaction conditions. These include ethers,such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether,or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexaneor mineral oil fractions, or halogenated hydrocarbons, such asdichloromethane, trichloromethane, carbon tetrachloride,dichloroethylene, trichloroethylene or chlorbenzene, or ethyl acetate,pyridine, dimethyl sulphoxide, dimethylformamide,N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidone (NMP),acetonitrile, acetone or nitromethane. It is also possible to usemixtures of the solvents mentioned.

[0178] Bases suitable for the process according to the invention are, ingeneral, inorganic or organic bases. These preferably include alkalimetal hydroxides, such as, for example, sodium hydroxide or potassiumhydroxide, alkaline earth metal hydroxides, such as, for example, bariumhydroxide, alkali metal carbonates, such as sodium carbonates, potassiumcarbonate or caesium carbonate, alkaline earth metal carbonate, such ascalcium carbonate, or alkali metal or alkaline earth metal alkoxides,such as sodium methoxide or potassium methoxide, sodium ethoxide orpotassium ethoxide or potassium tert-butoxide, or organic amines, suchas triethylamine, or heterocycles, such as 1,4-diazabicyclo[2.2.2]octane(DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, diaminopyridine,N-methylpiperidine or N-methyl-morpholine. It is also possible to usealkali metals such as sodium or their hydrides, such as sodium hydride,as bases.

[0179] Preferred solvents for process step [A] (II)+(III)→(IV) arediethyl ether, tetrahydrofuran and dimethylformamide. Particularpreference is given to dimethylformamide.

[0180] Preferred bases for process step [A] (II)+(III)→(IV) are sodiumhydride and sodium hydroxide.

[0181] In general, the base is employed in an amount of from 0.05 mol to10 mol, preferably from 1 mol to 2 mmol, based on 1 mol of the compoundof the formula (II).

[0182] The process step [A] according to the invention, (II)+(III)→(IV),is generally carried out in a temperature range of from −20° C. to +100°C., in particular from −20° C. to +80° C., preferably from 0° C. to +80°C.

[0183] The hydrolysis of carboxylic esters in process step [A] (IV)→(V)is carried out by customary methods by treating the esters in inertsolvents with bases, and converting the salts which are initially formedinto the free carboxylic acids, by treatment with acid. In the case ofthe tert-butyl esters, the hydrolysis is preferably carried out usingacids.

[0184] Solvents suitable for the hydrolysis of the carboxylic esters arewater or the organic solvents which are customary for ester hydrolysis.These preferably include alcohols, such as methanol, ethanol, propanol,isopropanol or butanol, or ethers, such as tetrahydrofuran or dioxane,dimethylformamide, dichloromethane or dimethyl sulphoxide. It is alsopossible to use mixtures of the solvents mentioned. Preference is givento water/tetrahydrofuran and, in the case of the reaction withtrifluoroacetic acid, dichlormethane and, in the case of hydrogenchloride, tetrahydrofuran, diethyl ether, dioxane or water.

[0185] Suitable bases are the inorganic bases customary for hydrolysis.These preferably include alkali metal hydroxides or alkaline earth metalhydroxides, such as, for example, sodium hydroxide, lithium hydroxide,potassium hydroxide or barium hydroxide, or alkali metal carbonates,such as sodium carbonate or potassium carbonate, or sodium bicarbonate.Particular preference is given to using sodium hydroxide or lithiumhydroxide.

[0186] Suitable acids are, in general, trifluoroacetic acid, sulphuricacid, hydrogen chloride, hydrogen bromide and acetic acid, or mixturesthereof, if appropriate with addition of water. Preference is given tohydrogen chloride or trifluoroacetic acid in the case of the tert-butylesters and to hydrochloric acid in the case of the methyl esters.

[0187] When carrying out the hydrolyses, the base or the acid isgenerally employed in an amount of from 1 to 100 mol, preferably from1.5 to 40 mol, based on 1 mol of ester.

[0188] The hydrolysis is generally carried out in a temperature range offrom 0° C. to +100° C.

[0189] The amide formation in process step [A] (V)+(VI)→(I) ispreferably carried out in the solvent dimethylformamide ordichloromethane.

[0190] Preferred auxiliaries used for the amide formation are customarycondensing agents, such as carbodiimides, for example N,N′-diethyl-,N,N,′-dipropyl-, N,N′-diisopropyl-, N,N′-dicyclohexylcarbodiimide,N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), orcarbonyl compounds, such as carbonyldiimidazole, or 1,2-oxazoliumcompounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulphate or2-tert-butyl-5-methyl-isoxazolium perchlorate, or acylamino-compounds,such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, orpropanephosphonic anhydride, or isobutyl chloroformate, orbis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride orbenzotriazolyloxy-tri(dimethylamino)phosphonium hexafluorophosphate, orO-(benzotriazol-1-yl)-N,N,N′,N′-tetra-methyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU) orO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), if appropriate in combination with furtherauxiliaries, such as 1-hydroxybenzotriazole or N-hydroxysuccinimide, andthe bases used are preferably alkali metal carbonates, for examplesodium carbonate or potassium carbonate, or sodium bicarbonate orpotassium bicarbonate, or organic bases, such as trialkylamines, forexample triethylamine, N-methylmorpholine, N-methylpiperidine ordiisopropylethylamine. Particular preference is given to the combinationof EDC, N-methylmorpholine and 1-hydroxybenzotriazole.

[0191] The amide formation is generally carried out a temperature rangeof from 0° C. to +100° C.

[0192] Solvents suitable for the acylation in process step [B] (VII)→(I)are the customary solvents which are inert under the reactionconditions; preference is given here to dimethylformamide anddichloromethane.

[0193] Suitable bases used for the acylation, if appropriate, are thecustomary inorganic or organic bases, preferably triethylamine.

[0194] The acylation is generally carried out in a temperature range offrom 0° C. to +100° C.

[0195] The compounds of the formulae (II), (III), (VI), (VIII), (IX) and(X) are known or can be prepared by customary methods (cf. EP-A-0 725061, EP-A-0 725 064, EP-A-0 581 003, EP-A-0 611 767, WO-A-00/73274).

[0196] The compounds of the formula (VII) can be prepared by convertingcompounds of the formula (II) with compounds of the formula (XI)

Y-A-H  (XI),

[0197] in which

[0198] A represents an oxygen atom or a group of the formula N—R⁵,

[0199] where R⁵ is as defined above,

[0200] and

[0201] Y represents a suitable amino or hydroxyl protective group,

[0202] if appropriate in the presence of a base, into compounds of theformula (XII)

[0203] in which

[0204] A, D, T and Y are as defined above,

[0205] in the next steps, analogously to the reaction steps describedunder [A], initially converting these by hydrolysis into compounds ofthe formula (XIII),

[0206] in which

[0207] A, D and Y are as defined above,

[0208] then reacting with compounds of the formula (VI) to givecompounds of the formula (XIV)

[0209] in which

[0210] A, D, Y, R³ and R⁴ are as defined above,

[0211] and finally removing the protective group Y by customary methods.

[0212] The preparation of compounds of the formula (VII) can beillustrated in an exemplary manner by the equation below:

[0213] The conversion (II)+(XI)→(XII) is carried out in the customarysolvents which are inert under the reaction conditions. Preference isgiven to acetonitrile.

[0214] Suitable bases, which are used for this reaction, if appropriate,are the customary inorganic or organic bases.

[0215] The reaction is generally carried out in a temperature range offrom 0° C. to +100° C.

[0216] Surprisingly, the compounds of the formula (I) according to theinvention have an unforeseeable useful pharmacological activityspectrum, combined with improved administration properties.

[0217] The compounds according to the invention act as adenosine-uptakeinhibitors. They can be used for preparing medicaments for theprevention and/or treatment of peripheral and cardiovascular disorderscaused by ischaemia, in particular for the acute and chronic treatmentof ischaemic disorders of the cardiovascular system, such as, forexample, coronary heart disease, stable and unstable angina pectoris, ofperipheral and arterial occlusive diseases, of thrombotic vascularocclusions, of myocardial infarction and of reperfusion damage.

[0218] Moreover, owing to their potential to increase angiogenesis, theyare particularly suitable for a permanent therapy of all occlusivediseases.

[0219] In addition, the compounds according to the invention, alone orin combination with other medicaments, can be used by oral orintravenous administration for preventing and/or treating cerebralischaemia, stroke, reperfusion damage, brain trauma, oedema, spasms,epilepsy, respiratory arrest, cardiac arrest, Reye syndrome, cerebralthrombosis, embolism, tumours, haemorrhages, encephalomyelitis,hydroencephalitis, spinal injuries, post-operative brain damage,injuries of the retina or the optical nerve following glaucoma,ischaemia, hypoxia, oedema or trauma, and also in the treatment ofschizophrenia, sleep disturbances and acute and/or chronic pain and alsoneurodegenerative disorders, in particular for the treatment ofcancer-induced pain and chronic neuropathic pain, such as, for example,in cases of diabetic neuropathy, posttherpeutic neuralgia, peripheralnerve damage, central pain (for example as a result of cerebralischaemia) and trigeminal neuralgia and other chronic pain, such as, forexample, lumbago, lower back pain or rheumatic pain.

[0220] Adenosine-uptake inhibitors like the compounds according to theinvention can furthermore also be used for treating hypertension andcardiac insufficiency, myocarditis, nephritis, pancreatitis, diabeticnephropathy, oedema and for potentiating the effect of nucleobase,nucleoside or nucleotide antimetabolites in cancer chemotherapy andantiviral (for example HIV) chemotherapy.

[0221] The compounds according to the invention have an increasedsolubility in water and an improved bioavailability, in particular whenadministered orally. These advantageous properties can, if appropriate,be improved even further with the aid of formulation auxiliaries and/orby adjusting a suitable pH. Good solubility in water and highbioavailability are, as is known, advantageous properties in medicinallyactive compounds and formulations; thus, the compounds according to theinvention are, for example, particularly suitable for oral andintravenous administration.

[0222] A Assessment of the Physiological Activity

[0223] 1. Determination of the Solubility

[0224] To determine the solubility, a precipitation method was used:

[0225] 10 mg of the test substance are completely dissolved in 50 μl ofDMSO (stock solution), 20 μl of this solution are added to 2000 μl ofphysiological saline. This solution, in turn, is shaken at 25° C. in aThermomixer Comfort (from Eppendorf) at 1400 rpm for 24 hours forequilibration.

[0226] The precipitated fractions of the test substance are centrifugedoff using a Biofuge 15 from Heraeus at 14,000 rpm for 5 min. 1300 μl ofthe supernatant are once more centrifuged using a Microfuge fromBeckmann at 45,000 rpm=125,000 g.

[0227] 10 μl of this centrifugation supernatant are then diluted with1000 μl of DMSO, and this solution is measured by HPLC (Hewlett Packard1090, method: gradient from 100% PBS buffer pH=4 to 10% buffer/90%acetonitrile over a period of 15 min, column: RP18)

[0228] Using a calibration curve, the measured peak area of the HPLCmeasurement is converted into the substance concentration. For thecalibration curve, 20 μl of the stock solution are diluted successivelywith DMSO such that 5 concentrations of 2.5 mg/l to 2000 mg/l result.These solutions are likewise measured by HPLC (see method above), andthe peak areas are plotted as a function of the concentrations.

[0229] 2. Inhibition of the Adenosine Uptake in Rabbit Erythrocytes bythe Compounds According to the Invention

[0230] The capability of substances to influence the adenosine-uptakesystem is investigated by determining the inhibitory effect of thesubstances on functional adenosine uptake.

[0231] For the functional adenosine-uptake test, an erythrocytepreparation from rabbit blood is used. The blood is drawn intravenouslyusing citrate (3 ml Monovette 9NC from Sarstedt) as anticoagulant. Theblood is centrifuged at 3000 g for 5 min and the erythrocytes aresuspended in 10 mM 3-(N-morpholino)propanesulphonic acid buffer(MOPS)/0.9% NaCL solution pH7.4. The suspension is diluted to onehundredth of the original blood volume. In each case, 990 μl of thesuspension are admixed with 10 μl of a suitable concentration of thesubstance to be investigated, and the mixture is incubated at 30° C. for5 min. 5 μl of a 4 mM adenosine solution are then added, and the mixtureis incubated at 30° C. for another 15 min. The samples are thencentrifuged at 3000 g for 5 min and in each case 700 μl of thesupernatant are admixed with 28 μl of 70% strength HClO₄, allowed tostand in an ice bath for 30 min and centrifuged at 16,000 g for 3 min,and 350 μl of the sample are neutralized using 30 μl of 5N NaOH. 50 μlof the sample are applied to a column (Waters Symmetry C18 5 μm 3.9×150mm). A Spherisorb ODS II 5 μm 4.6×10 mm column is used as precolumn. Themobile phase used is a gradient of 50 M KH₂PO₄/5 mM tributylamine pH7(mobile phase A) and a mixture of mobile phase A/methanol 1/1 (mobilephase B). The gradient is from 10 to 40% B, at a flow rate of 0.5ml/min. The adenosine which is present is quantified by its absorptionat 260 nm, as are the hypoxanthine and inosine formed. The IC₅₀ is theconcentration of active compound at which, 15 min after addition ofadenosine, 50% of the adenosine concentration originally employed isstill present.

[0232] Using this test, the IC₅₀ value determined for Example 1-1 was 30nM, that for Example 1-3 was 20 nM, that for Example 1-14 was 30 nM,that for Example 1-33 was 40 nM, that for Example 2-1 was 20 nM and thatfor Example 2-18 was 20 nM.

[0233] 3. In Vivo Test Model for Testing Adenosine-Uptake Inhibitors

[0234] Adult FBI (Foxhound-Beagle-Irish-Setter) dogs (20-30 kg) areinitially anaesthetized using a combination of trapanal 500 mg andalloferin 55 mg. Anaesthesia is maintained by infusion of a mixture offentanyl 0.072 mg/kg, alloferin 0.02 mg/kg and dihydrobenzpyridyl 0.25mg/kg×min. The animals are intubated and ventilated with a mixture ofO₂/N₂O ⅕ using an Engstrom ventilation pump at 16 breaths per min and avolume of 18-24 ml/kg. The body temperature is maintained at 38° C.±0.1°C. Arterial blood pressure is measured via a catheter in the femoralartery. Thoractomy is carried out on the left side at the fifthintercostal space. The lung is pushed back and fixed and a cut is madein the pericardium. A proximal section of the LAD distally to the firstdiagonal branch is exposed and a calibrated electromagnetic flow sensor(Gould Statham, model SP7515) is placed around the vessel and attachedto a flow meter (Statham, model SP-2202). Distally to the flow sensor, amechanical occluder is attached such that there are no branches inbetween flow sensor and occluder.

[0235] Using a catheter in the femoral vein, blood samples are taken andsubstances administered. A peripheral ECG is recorded using needleswhich are fixed subcutaneously. A microtip pressure manometer (Millarmodel PC-350) is pushed through the left atrium to measure the pressurein the left ventricle. Measurement of the heart frequency is triggeredby the R wave of the ECG. During the entire experiment, the haemodynamicparameters and coronary flow are recorded using a multi-event recorder.

[0236] A four-minute occlusion causes reactive hyperaemia. Thedifference between the coronary flow under control conditions and themaximum flow during the reactive hyperaemia is measured. The time whichis required to achieve half of this maximum flow in the drop is asuitable parameter to assess the reactive hyperaemia.

[0237] After a stabilization period of one hour, the experiment isstarted with a four-minute occlusion. Thirty minutes later, thesubstance is administered (i.v.) which is, after two minutes, followedby re-occlusion. The reactive hyperaemia after verum and placebo iscompared.

[0238] 4. Measurement of the Plasma Concentration of Adenosine-UptakeInhibitors Following Oral Administration to Mice

[0239] Test principle: Following oral administration, blood samples aretaken from the mice and the concentration of the active compound in theblood is measured by the functional inhibition of the adenosine uptakein rabbit erythrocytes.

[0240] The substances were administered in a dosage of 10 mg/kg and anadministration volume of 10 ml/kg using a stomach tube. The solvent usedwas polyethylene glycol 400/ethanol 9:1. After one hour, the animalswere anaesthetized and, by puncture of the heart, about 0.5 to 0.7 ml ofblood were taken. The blood was precipitated in 5 times its volume ofacetonitrile, kept in an ice bath for 30 minutes and then centrifuged at16,000 g in an Eppendorf centrifuge for 5 minutes. At room temperature,the supernatant was evaporated to dryness in a Speedvac. The driedsamples were initially wetted with 20 μl of DMSO and then admixed with 1ml of 10 mM of 3-(N-morpholino)propanesulphonic acid buffer (MOPS)/0.9%aqueous sodium chloride solution pH7.4 and kept in an ultrasonic bathfor 15 minutes. They were then centrifuged at 16,000 g for 5 minutes.

[0241] In each case, 500 μl of extract; 200 μl of extract and 300 μl ofthe above-mentioned buffer; 100 μl of extract and 400 μl of buffer; 50μl of extract and 450 μl of buffer were mixed with a suspension of ineach case 500 μl of rabbit erythrocytes. [The erythrocytes were isolatedas described under Experiment 2 (“Inhibition of the adenosine uptake inrabbit erythrocytes”) and diluted to fifty times the original bloodvolume]. As described under Experiment 2, adenosine was added after 5minutes and the adenosine uptake was measured. The inhibition ofadenosine uptake can be used to calculate the concentration of theinhibitor in the sample, since the inhibitory effect of theadenosine-uptake inhibitor was determined beforehand by a concentrationcurve using the method described in Experiment 2.

[0242] 5. Mouse Angiogenesis Model

[0243] To test the effect of the adenosine-uptake inhibitors oncollateralization and neovascularization, a mouse model for angiogenesiswas developed. To this end, a femoral artery of the mouse is ligated atthe upper end of the thigh. This induces chronic ischaemia of the hindleg in question. The other hind leg serves as individual control. Toexclude residual flow through the ligated vessel, two ligatures areapplied, and the vessel is cut in between. A few days after thisoperation, the treatment is started.

[0244] As a measurement parameter during the ongoing experiment, thetemperatures of the paws of the two hind legs are measured. Owing topoorer circulation, the ischaemic hind leg has a lower absolutetemperature. In each case, the temperature difference between the pawsof the hind legs is calculated. This individual temperature differenceis determined in various treatment groups as a function of the dose andin comparison with an untreated control. In this model, adenosine-uptakeinhibitors significantly improve the circulation of the ischaemic hindleg in comparison with the corresponding controls.

[0245] The novel active compounds can be converted in a known mannerinto the customary formulations, such as tablets, sugar-coated tablets,pills, granules, aerosols, syrups, emulsions, suspensions and solutions.In this connection, the therapeutically active compound should in eachcase be present in a concentration of approximately 0.5 to 90% by weightof the total mixture, i.e. in amounts which are sufficient in order toachieve the dosage range indicated. In addition to the active compoundsof the formula (I), the formulations may also comprise otherpharmaceutically active compounds.

[0246] The formulations are prepared, for example, by extending theactive compounds with inert non-toxic pharmaceutically suitableauxiliaries. Auxiliaries which may be mentioned are, for example: water,non-toxic organic solvents, such as, for example, paraffins, vegetableoils (for example sesame oil), alcohols (for example ethanol, glycerol),glycols (for example polyethylene glycol), solid carriers, such asnatural or synthetic ground minerals (for example talc or silicates),sugar (for example lactose), emulsifiers, dispersants (for examplepolyvinylpyrrolidone) and glidants (for example magnesium sulphate).

[0247] Administration is carried out in a customary manner, preferablyorally, transdermally, parenterally, perlingually, intravenously;particularly preferably orally or intravenously.

[0248] In general, it has proven advantageous in the case of intravenousadministration to administer amounts of approximately 0.0001 to 10mg/kg, preferably approximately 0.003 to 1 mg/kg, of body weight, toachieve effective results. In the case of oral administration, 0.1 to 20mg/kg, preferably 0.3 to 10 mg/kg, of body weight are employed.

[0249] In spite of this, if appropriate, it may be necessary to departfrom the amounts mentioned, namely depending on the body weight or onthe type of administration route, on the individual response towards themedicament, the manner of its formulation and the time or interval atwhich administration takes place. Thus, in some cases it may be adequateto manage with less than the above-mentioned minimum amount, while inother cases the upper limit mentioned has to be exceeded. It may beadvisable to divide this amount into a number of individual doses overthe course of the day or to have a delayed release of active compoundfrom the formulation over a relatively long period of time.

[0250] Below, the present invention is illustrated using the followingpreferred examples; however, these examples do not limit the inventionin any way.

[0251] Unless indicated otherwise, all amounts are in percent by weight;in the case of solvent mixtures, ratios by volume are given.

B PREPARATION EXAMPLES

[0252] In the examples, the following abbreviations are used:

[0253] DMF=N,N-dimethylformamide

[0254] DMSO=dimethyl sulphoxide

[0255] TFA=trifluoroacetic acid

[0256] THF=tetrahydrofuran

[0257] EDC═N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride

[0258] HOBT=1-hydroxybenzotriazole

[0259] DMAP=4-dimethylaminopyridine

[0260] TBDMS=tert-butyl-dimethylsilyl

[0261] BOC=tert-butyloxycarbonyl

[0262] Starting Materials

Example I

[0263]tert-Butyl(1R,2R)-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylate:

[0264] The intermediate is prepared analogously to the procedure for theracemate (U.S. Pat. No. 5,395,840, column 17). For purification, theresulting mixture is stirred with diethyl ether or diisopropyl ether.

Example II

[0265] (2S)-2-Amino-4-(methylsulphonyl)butanamide Hydrochloride

[0266] a) N²-(tert-Butoxycarbonyl)-L-methionineamide

[0267] Under argon, 8.12 g (80.2 mmol) of triethylamine are added at−15° C. to 20 g (80.2 mmol) of N-Boc-L-methionine in 200 ml of THF. Overa period of 5 min, 10.4 ml (80,2 mmol) of isobutyl chloroformate areadded dropwise, and the reaction mixture is stirred at −15° C. for 30min. 40 ml of 2N ammonia solution in methanol are then added and themixture is stirred in the cold for 30 min. The reaction mixture isfiltered, the filtrate is concentrated under reduced pressure and theresidue is stirred with 200 ml of water for 1 hour. The solid isfiltered off with suction, dissolved in 250 ml of dichloromethane andwashed twice with sat. sodium bicarbonate solution, and the solvent isagain removed under reduced pressure. The residue is stirred with 0.7 lof petroleum ether, filtered off with suction and dried under highvacuum. This gives 12.86 g (64.6% of theory) of product as a crystallinesubstance.

[0268] R_(f) (dichloromethane/methanol 10:1)=0.52.

[0269] MS (DCI, NH₃)=249 [(M+H)⁺; 68%]; 266 [(M+NH₄)⁺; 100%].

[0270]¹H-NMR (200 MHz, DMSO-d₆) δ [ppm]=1.38 (s, 9H); 1.65-1.95 (m, 2H);2.04 (s, 3H); 2.44 (br. t, 2H); 3.93 (dt, 1H); 6.88 (d, 1H); 6.99 (br.s, 1H); 7.25 (br. s, 1H).

[0271] b)tert-Butyl(1S)-1-(aminocarbonyl)-3-(methylsulphonyl)propylcarbamate

[0272] At 0° C., 29.9 g (98.7 mmol) of 3-chloroperbenzoic acid are addeda little at a time to 12.25 g (49.3 mmol) of the compound from ExampleII-a in 50 ml of dichloromethane and 15 ml of methanol. After 2 hours,saturated sodium hydrogen sulphite solution is added and the mixture isstirred at room temperature for one hour. The phases are separated, theaqueous phase is extracted twice with dichloromethane and the combinedorganic phases are washed with saturated sodium bicarbonate solution.After drying over sodium sulphate and removal of the solvent underreduced pressure, 2.36 g (9.4%) of product are isolated. The sodiumbicarbonate solution is then extracted twice with ethyl acetate, thecombined organic phases are dried over sodium sulphate and the solventis removed under reduced pressure, giving 7.38 g (46.6%) of productwhich still contains small amounts of benzoic acid.

[0273] Concentration of the sodium bicarbonate solution and extractionof the residue with water and ethyl acetate, two extractions of theaqueous phase with ethyl acetate and drying of the extract over sodiumsulphate give further 0.65 g (4.4%) of product. The combined productfractions are reacted further without further purification.

[0274] R_(f) (dichloromethane/methanol 10:1)=0.49.

[0275] MS (ESI-pos.)=281 [(M+H)⁺; 18%]; 303 [(M+Na)⁺; 100%]; 583[(2M+Na)⁺, 50%].

[0276]¹H-NMR (200 MHz, DMSO-d₆) δ [ppm]=1.38 (s, 9H); 1.72-2.14 (m, 2H);2.97 (s, 3H); 3.08 (m, 2H); 3.97 (m, 1H); 6.96 (d, 1H); 7.17 (br. s,1H); 7.34 (br. s, 1H).

[0277] c) (2S)-2-Amino-4-(methylsulphonyl)butanamide Hydrochloride

[0278] 10.25 g (36.56 mmol) of the compound from Example II-b aredissolved in 20 ml of dioxane and stirred at room temperature with 50 ml4N HCl in dioxane for 1 hour. A further 50 ml of 4 N HCl in dioxane areadded, and the mixture is then stirred at room temperature overnightuntil the reaction has gone to completion. The precipitated solid isfiltered off with suction and washed with petroleum ether. 6.96 g (62.5%of theory) of product are isolated as a colourless solid.

[0279] MS (ESI-pos.)=181 [(M+H)⁺; 100%]; 203 [(M+Na)⁺; 18%].

[0280]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]=2.19 (m, 2H); 3.04 (s, 3H); 3.22(m, 2H); 3.89 (t, 1H); 7.67 (br.s, 1H); 8.08 (br. s, 1H); 8.38 (br. s,3H).

[0281] General Alkylation Procedure [A]:

[0282] In a typical reaction, a solution of the compound of the formula(III) (4.12 mmol) in dry DMF (6 ml) is added to a suspension of sodiumhydride (4.33 mmol) in dry DMF (6 ml). The mixture is stirred at roomtemperature for 30 min and at 40° C. for 30 min, and a suspension of thecompound of the formula (II) (4.12 mmol) in dry DMF (15 ml) is thenadded. The mixture is stirred at room temperature for 24 hours and thecrude mixture is then added to distilled water (200 ml). The milkyemulsion is admixed with 2 g of sodium chloride and extracted four timeswith in each case 40 ml of diethyl ether. The combined organic phasesare washed three times with in each case 30 ml of saturated sodiumchloride solution and dried over sodium sulphate. Followingchromatography (silica gel, cyclohexane:ethyl acetate), the product isobtained in a yield of from 60 to 96%.

[0283] General Procedure for Ester Hydrolysis [B]:

[0284] In a typical reaction, a solution of the ester of the formula(IV) (T=tert-Bu; 24.5 mmol) in 46 ml of dichloromethane is treated atroom temperature with 23 ml of trifluoroacetic acid, and the mixture isstirred at room temperature for 16 hours. The solvent is removed underreduced pressure and the residue is taken up in 150 ml of diethyl ether,admixed with 200 ml of water and adjusted to pH12 using 1 N aqeuoussodium hydroxide solution (about 70 ml). The phases are separated andthe aqueous phase washed twice with in each case 100 ml of diethylether. Using 5N hydrochloric acid, the mixture is acidified to pH3 andextracted three times with in each case 150 ml of dichloromethane. Thecombined organic phases are dried over sodium sulphate and concentratedunder reduced pressure, giving the product in a yield of from 90 to 98%.

[0285] General Procedure for the Amide Formation [C]:

[0286] In a typical reaction, a mixture of the acid of the formula (V)(3.96 mmol), 1-hydroxybenzotriazole (3.96 mmol), EDC hydrochloride (4.75mmol) and 4-dimethylaminopyridine (0.33 mmol) is admixed with dry DMF(10 ml). The mixture is stirred at room temperature for 5 minutes, andN-methylmorpholine (11.9 mmol) and (S)-phenylglycinamide hydrochloride(4.75 mmol) are then added. The mixture is stirred at room temperaturefor three days and chromatographed by reversed-phase HPLC, and theresulting product fraction is then lyophilized. The desired product isobtained in a yield of from 60 to 90%.

SYNTHESIS EXAMPLES Example 1-1

[0287]N-{4-[(1R,2R)-2-({[(1S)-2-Amino-2-oxo-1-phenylethyl]amino}carbonyl)cyclohexyl]benzyl}-N-phenyl-4-morpholinecarboxamide:

[0288] a) N-Phenyl-4-morpholinecarboxamide:

[0289] A solution of 7.44 g (85.4 mmol) of morpholine in 35 ml of abs.dichloromethane is cooled to 0° C. A solution of 9.25 g (77.7 mmol) ofphenyl isocyanate in 15 ml of abs. dichloromethane is added dropwise(over a period of 5 min). The mixture is stirred at 0° C. for 30 min andat room temperature overnight. The product precipitates in the form ofwhite crystals. The crystals are filtered off, washed twice with in eachcase 20 ml of diethyl ether and dried under high vacuum: 11.1 g of whitecrystals (69% of theory).

[0290] R_(f) (dichloromethane/methanol 20:1)=0.38.

[0291] MS (DCI, NH₃)=224 (M+NH₄)⁺.

[0292]¹H-NMR (300 MHz, CDCl₃) δ[ppm]: 3.46 (4H, t), 3.72 (4H, t), 6.39(1H, br. s), 7.05 (1H, tt), 7.23-7.38 (4H, m).

[0293] b)tert-Butyl(1R,2R)-2-(4-{[(4-morpholinylcarbonyl)(phenyl)amino]-methyl}phenyl)cyclohexanecarboxylate:

[0294] A solution of 850 mg (4.12 mmol) of the compound from Example1-1a in 6 ml of DMF is added dropwise to a suspension of 173 mg (60% inmineral oil, 4.33 mmol) of sodium hydride in 4 ml of DMF. The mixture isstirred at room temperature for 30 min, and a suspension of 1.62 g (90%,4.12 mmol) oftert-butyl(1R,2R)-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylatefrom Example I in 15 ml of DMF is then added dropwise. The mixture isstirred at room temperature for 24 hours and the crude mixture is thenadded to 200 ml of dist. water. The milky emulsion is admixed with 2 gof sodium chloride and extracted four times with in each case 40 ml ofdiethyl ether. The combined organic phases are washed three times within each case 30 ml of saturated sodium chloride solution and dried oversodium sulphate. The yellow oily crude product is purified by columnchromatography (silica gel (70-230 mesh), gradient from cyclohexane tocyclohexane/ethyl acetate=2:1). This gives 1.89 g (96% of theory) of acolourless oil which solidifies under high vacuum.

[0295] R_(f) (cyclohexane/acetic acid 2:1)=0.17.

[0296] MS (ESI)=479 (M+H)⁺.

[0297]¹H-NMR (200 MHz, DMSO-d₆) 8[ppm]: 1.00 (9H, s), 1.20-1.53 (4H, m),1.58-1.92 (4H, m), 2.30-2.60 (2H, m), 3.04-3.16 (4H, m), 3.33-3.43 (4H,m), 4.78 (2H, s), 6.98-7.32 (9H, m).

[0298] c)(1R,2R)-2-(4-{[(4-Morpholinylcarbonyl)(phenyl)amino]methyl}phenyl)-cyclohexanecarboxylicAcid:

[0299] A solution of 11.75 g (24.5 mmol) of the compound from Example1-1b in 46 ml of dichloromethane is treated with 23 ml oftrifluoroacetic acid and stirred at room temperature for 16 hours. Thesolvent is distilled off under reduced pressure and the residue is, ineach case twice, dissolved in 10 ml of dichloromethane, admixed with 30ml of cyclohexane and concentrated under reduced pressure.

[0300] The residue is dissolved in 150 ml of diethyl ether, admixed with200 ml of water and adjusted to pH12 using 70 ml of 1N NaOH. The phasesare separated and the aqueous phase is washed twice with in each case100 ml of diethyl ether. Using 5N hydrochloric acid, the mixture isacidified to pH=3 and extracted three times with in each case 150 ml ofdichloromethane. The extracts are dried using sodium sulphate and thesolvent is removed under reduced pressure. The residue is dissolved in20 ml of diethyl ether and re-concentrated. This gives 10.1 g (95% oftheory) of the product in the form of a white solid foam.

[0301] R_(f) (dichloromethane/methanol 10:1)=0.39.

[0302] MS (ESI)=423 (M+H)⁺.

[0303]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 1.20-1.54 (4H, m), 1.58-1.83(3H, m), 1.85-2.03 (1H, m), 2.40-2.50 (2H, m), 3.05-3.18 (4H, m),3.30-3.44 (4H, m), 4.77 (2H, s), 7.00-7.34 (9H, m), 11.74 (1H, br. s).

[0304] d)N-{4-[(1R,2R)-2-({[(1S)-2-Amino-2-oxo-1-phenylethyl]amino}carbonyl)-cyclohexyl]benzyl}-N-phenyl-4-morpholinecarboxamide:

[0305] 10 ml of abs. DMF are added to a mixture of 1.67 g (3.96 mmol) ofthe compound from Example 1-1c, 535 mg (3.96 mmol) of HOBT, 910 mg (4.75mmol) of EDC and 40 mg of DMAP. The mixture is stirred at roomtemperature for 5 min until a clear solution is formed. 1.31 ml (1.20 g,11.88 mmol) of N-methylmorpholine and 0.886 g (4.75 mmol) ofL-phenylglycinamide hydrochloride are then added. The mixture is stirredat room temperature for 3 days and then separated directly by RP-HPLC(C18 Gromsil, 250 mm×30 mm, 50 ml/min, gradient water/acetonitrile90:10→wasser/acetonitrile 10:90 in 30 min, 4.5 ml solution of the crudemixture per separation). The acetonitrile is removed under reducedpressure and the product separates out as a slightly pink sticky solid.It is frozen and lyophilized overnight. This gives 1.80 g (82% oftheory) of the product as a white solid.

[0306] R_(f) (dichloromethane/methanol 20:1)=0.20.

[0307] MS (ESI)=555 (M+H)⁺.

[0308]¹H-NMR (300 MHz, DMSO-d₆) δ[ppm]: 1.20-1.54 (4H, m), 1.61-1.87(4H, m), 2.59-2.70 (1H, m), 2.75-2.86 (1H, m), 3.12 (4H, t), 3.38 (4H,t), 4.79 (2H, s), 5.17 (1H, d), 6.80-6.89 (2H, m), 7.02-7.15 (1H, m),7.28 (2H, t), 7.58 (1H, br. s), 7.96 (1H, d).

Example 1-34

[0309] (1R,2R)-2-(4-{[Acetyl(2-pyridinyl)amino]methyl}phenyl)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]cyclohexanecarboxamide:

[0310] a)tert-Butyl(1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}phenyl)cyclohexanecarboxylate:

[0311] N-(2-Pyridinyl)acetamide (500 mg) is initially charged in dry DMF(25 ml), sodium hydride (116 mg, 80% in oil) is added at 0° C., and themixture is stirred at room temperature for 30 min and at 40° C. for 30min, cooled to 0° C. and treated a little at a time with the compoundfrom Example I (1.36 g). The mixture is stirred at room temperatureovernight and then hydrolyzed at 0° C. using water and extracted withdiethyl ether. The organic phases are dried with magnesium sulphate andthen concentrated. Subsequent chromatography (silica gel,cyclohexane:ethyl acetate 1:1 to 0:1) givestert-butyl(1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}-phenyl)cyclohexanecarboxylateas a colourless solid.

[0312] MS (ESI)=409 (M+H)⁺.

[0313]¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]: 1.0 (s, 9H), 1.2-1.49 (m, 5H),1.62-1.77 (m, 3H), 1.81-1.9 (m, 1H), 2.02 (s, 3H), 2.35-2.45 (m, 1H),5.02 (s, 2H), 7.05-7.13 (m, 4H), 7.2-7.27 (m, 1H), 7.37 (d, 1H), 7.48(td, 1H), 8.43 (dd, 1H).

[0314] b)(1R,2R)-2-(4-{[Acetyl(2-pyridinyl)amino]methyl}phenyl)cyclohexane-carboxylicAcid

[0315]tert-Butyl(1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}phenyl)cyclohexanecarboxylate(0.44 g) is dissolved in dichloromethane (3.4 ml) and trifluoroaceticacid (3.4 ml), stirred at room temperature for 2 hours and then, at 0°C., made alkaline using aqueous sodium hydroxide solution. The aqueousphase is washed with dichloromethane, acidified with hydrochloric acidand extracted with dichloromethane. The organic extracts are dried oversodium sulphate and concentrated. This gives(1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}-phenyl)cyclohexanecarboxylicacid (445 mg) as a viscous yellow oil.

[0316] MS (ESI)=353 (M+H)⁺; 375 (M+Na)⁺.

[0317]¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]: 1.21-1.5 (m, 4H), 1.62-1.8 (m,3H), 1.89-1.98 (m, 1H), 2.0 (s, 3H), 2.4-2.5 (m, 1H), 2.55-2.7 (m, 1H),5.0 (s, 2H), 7.05-7.13 (m, 4H), 7.24-7.3 (1H), 7.43 (d, 1H), 7.84 (td,1H), 8.47 (dd, 1H), 11.6 (broad s, 1H).

[0318] c)(1R,2R)-2-(4-{[Acetyl(2-pyridinyl)amino]methyl}phenyl)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]cyclohexanecarboxamide

[0319](1R,2R)-2-(4-{[Acetyl(2-pyridinyl)amino]methyl}phenyl)cyclohexanecarboxylicacid (0.44 g) is suspended in DMF (15 ml),(2S)-2-amino-2-phenylethanamide (0.37 g), triethylamine (0.68 ml),1-hydroxybenzotriazole (0.18 g) and EDC hydrochloride (0.27 g) areadmixed and the mixture is stirred at room temperature for 2 days. Thesuspension is diluted with water and extracted with dichloromethane andthe organic phases are washed with saturated sodium chloride solution,dried over sodium sulphate and concentrated. Chromatography (silica gel,dichloromethane:methanol:saturated aqueous ammonia solution=50:1:0.05 to20:1:0.05 gives(1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}phenyl)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]cyclohexanecarboxamide(0.39 g) as a colourless solid.

[0320] R_(f) (dichloromethane/methanol/saturated aqueous ammoniasolution 40:2:0.1)=0.43

[0321] MS (ESI)=485 (M+H)⁺; 507 (M+Na)⁺.

[0322]¹H-NMR (300 MHz, DMSO-d₆): δ[ppm]: 1.23-1.52 (m, 4H), 1.65-1.86(m, 4H), 2.01 (s, 3H), 2.59-2.84 (m, 2H), 5.04 (s, 2H), 5.15 (d, 1H),6.78 (d, 2H), 6.97-7.11 (m, 8H), 7.24-7.29 (m, 1H), 7.43 (d, 1H), 7.57(s, 1H), 7.80 (td, 1H), 7.93 (d, 1H), 8.45-8.48 (m, 1H).

[0323] The compounds listed in Table 1 below are prepared in ananalogous manner: TABLE 1 Example Structure Retention time (method) 1-2 

7.49 (D) 1-3 

7.17 (D) 1-4 

4.15 (A) 1-5 

4.63 (A) 1-6 

4.69 (A) 1-7 

4.80 (A) 1-8 

4.86 (A) 1-9 

4.44 (A) 1-10

4.57 (A) 1-11

4.87 (A) 1-12

4.82 (A) 1-13

4.52 (A) 1-14

4.15 (A) 1-15

4.21 (A) 1-16

4.01 (A) 1-17

4.52 (A) 1-18

4.58 (A) 1-19

4.33 (A) 1-20

4.30 (A) 1-21

4.53 (A) 1-22

4.64 (A) 1-23

4.69 (A) 1-24

4.43 (B) 1-25

4.41 (A) 1-26

4.46 (A) 1-27

4.17 (B) 1-28

3.96 (A) 1-29

4.18 (A) 1-30

4.12 (A) 1-31

3.67 (A) 1-32

3.91 (A) 1-33

3.87 (A)

Example 2-1

[0324](1R,2R)-N-[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(4-fluorophenyl)amino]methyl}phenyl)cyclohexanecarboxamide:

[0325] a) N-Ethyl-N′-(4-fluorophenyl)-N-(2-hydroxyethyl)urea:

[0326] At 0° C., 1.00 g (7.29 mmol) of 4-fluorophenyl isocyanate areadded dropwise to a solution of 720 mg (8.02 mmol) ofN-ethylethanolamine in 4 ml of dichloromethane.

[0327] After 10 min at 0° C., the mixture is stirred at room temperaturefor 2 hours. The solution is concentrated under reduced pressure and theresidue is dissolved in 20 ml of dichloromethane and treated with 400 mgof Amberlyst® 15. The mixture is stirred at room temperature for 15 min,filtered and concentrated under reduced pressure. This gives 1.50 g (91%of theory) of the product as a yellow oil.

[0328] R_(f) (dichloromethane/methanol 40:1)=0.29.

[0329] MS (ESI)=227 (M+H)⁺.

[0330]¹H-NMR (400 MHz, DMSO-d₆) δ[ppm]: 1.07 (3H, t), 3.28-3.39 (4H, m),3.56 (2H, t), 5.16 (1H, t), 7.0-7.09 (2H, m), 7.37-7.43 (2H, m), 8.44(1H, br. s).

[0331] b)N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-ethyl-N′-(4-fluorophenyl)-urea:

[0332] 1.30 ml (9.35 mmol) of triethylamine and a solution of 1.03 g(6.86 mmol) of TBDMS chloride in 5 ml of dichloromethane are added to asolution of 1.41 g (6.23 mmol) of the compound from Example 2-1a in amixture of 10 ml of dichloromethane and 1.5 ml of abs. DMF. The mixtureis stirred at room temperature for 18 hours and diluted with 30 ml ofdichloromethane. The mixture is washed three times with in each case 30ml of water, dried with sodium sulphate and concentrated under reducedpressure. This gives 2.00 g (94% of theory) of a colourless oil.

[0333] R_(f) (dichloromethane/methanol 40:1)=0.74.

[0334] MS (ESI)=341 (M+H)⁺.

[0335]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.00 (6H, s), 0.81 (9H, s), 1.04(3H, t), 3.27-3.41 (4H, m), 3.67 (2H, t), 6.94-7.09 (2H, m), 7.34-7.46(2H, m), 8.15 (1H, br. s).

[0336] c)tert-Butyl(1R,2R)-2-{4-[4-ethyl-2-(4-fluorophenyl)-8,8,9,9-tetramethyl-3-oxo-7-oxa-2,4-diaza-8-siladec-1-yl]phenyl}cyclohexanecarboxylate:

[0337] A solution of 443 mg (1.30 mmol) of the compound from Example2-1b in 3 ml of DMF is added dropwise to a suspension of 54.6 mg (60% inmineral oil, 1.37 mmol) of sodium hydride in 1 ml of DMF. The mixture isstirred at room temperature for 45 min, and a suspension of 510 mg (90%,1.30 mmol) oftert-butyl(1R,2R)-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylatefrom Example I in 3 ml of DMF is then added dropwise. The mixture isstirred at room temperature for 4 hours and then diluted with 50 ml ofwater and extracted three times with in each case 30 ml of diethylether. The combined organic phases are washed with 100 ml of saturatedsodium chloride solution and dried over sodium sulphate. The crudeproduct is purified by column chromatography (silica gel (70-230 mesh),gradient: from cyclohexane to cyclohexane/ethyl acetate 5:1). This gives621 mg (78% of theory) of the product as a colourless oil.

[0338] R_(f) (dichloromethane/methanol 40:1)=0.78.

[0339] MS (ESI)=613 (M+H)⁺.

[0340]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.06 (6H, s), 0.83 (3H, t), 0.84(9H, s), 0.99 (9H, s), 1.20-1.52 (4H, m), 1.59-1.92 (4H, m), 2.32-2.61(2H, m), 3.06 (2H, q), 3.15 (3H, t), 3.51 (2H, t), 4.67 (2H, s),7.00-7.22 (8H, m).

[0341] d)tert-Butyl(1R,2R)-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(4-fluorophenyl)amino]methyl}phenyl)cyclohexancarboxylate:

[0342] 345 μl (1.20 mmol) of a 1.1 M solution of tetra-n-butylammoniumfluoride in THF are added to a solution of 246 mg (0.40 mmol) of thecompound from Example 2-1c in 20 ml of THF. The mixture is stirred atroom temperature for 4 hours and then diluted with 100 ml of diethylether. The mixture is washed three times with in each case 25 ml of asemisaturated sodium chloride solution and once with 20 ml of a sat.sodium chloride solution. The combined wash solutions are extracted with20 ml of diethyl ether and the combined organic phases are dried withsodium sulphate. The crude product is purified by column chromatography(silica gel (70-230 mesh), gradient: from cyclohexane tocyclohexane/ethyl acetate 1:1). Yield: 201 mg of a colourless oil (95%of theory)

[0343] R_(f) (cyclohexane/acetic acid 1:1)=0.29.

[0344] MS (ESI)=499 (M+H)⁺.

[0345]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.83 (3H, t), 1.00 (9H, s),1.20-1.52 (4H, m), 1.60-1.92 (4H, m), 2.32-2.61 (2H, m), 2.91-3.17 (4H,m), 3.36 (2H, t), 4.61 (1H, t), 4.66 (2H, s), 7.00-7.22 (8H, m).

[0346] e)(1R,2R)-2-(4-{[{[Ethyl(2-hydroxyethyl)amino]carbonyl}(4-fluorophenyl)-amino]methyl}phenyl)cyclohexanecarboxlicAcid:

[0347] 200 mg (0.40 mmol) of the compound from Example 2-1d aredissolved in 2 ml of dichloromethane and treated with 1 ml oftrifluoracetic acid. The solution is stored at 6° C. for 16 hours, and15 ml of 1N sodium hydroxide solution and 20 ml of water are then added.The mixture is washed twice with in each case 20 ml of diethyl ether andadjusted to pH3-4 using 1N hydrochloric acid. The mixture is extractedthree times with in each case 30 ml of dichloromethane and the extractsare dried with sodium sulphate and concentrated. The residue is taken upin 4 ml of diethyl ether and re-concentrated. The oil that is initiallyobtained turns into a white solid foam. Yield: 146 mg (78% of theory,94% purity according to HPLC).

[0348] R_(f) (dichloromethane/methanol 40:1)=0.44.

[0349] MS (ESI)=443 (M+H)⁺.

[0350]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.83 (3H, t), 1.20-1.52 (4H, m),1.60-1.82 (3H, m), 1.88-2.02 (1H, m), 2.40-2.72 (2H, m), 2.99-3.20 (4H,m), 3.34 (2H, t), 4.64 (2H, s), 7.03-7.20 (8H, m), 11.70 (1H, br. s)

[0351] f)(1R,2R)-N-[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(4-fluorophenyl)amino]methyl}phenyl)-cyclohexanecarboxamide:

[0352] 0.90 ml of abs. DMF is added to a mixture of 44.3 mg (0.100 mmol)of the compound from Example 2-1e, 13.5 mg (0.100 mmol) of HOBT, 23.0 mg(0.120 mmol) of EDC and 1 mg of DMAP. The mixture is stirred at roomtemperature for 5 min until a clear solution is formed. 22.0 μl (20.2mg, 0.200 mmol) of N-methylmorpholine and 30.7 mg (0.150 mmol) ofL-4-fluorophenylglycinamide hydrochloride are then added. The mixture isstirred at room temperature for 3 days and then separated directly byRP-HPLC (C18 Gromsil, 50×20 mm, 25 ml/min, gradient water/acetonitrile90:10→water/acetonitrile 10:90 over 8 min). The acetonitrile is removedunder reduced pressure and the product precipitates out in the form ofwhite flakes. The product is frozen and lyophilized overnight. Thisgives 37.9 mg (64% of theory) of the product as a white solid.

[0353] R_(f) (dichloromethane/methanol 10:1)=0.37.

[0354] MS (ESI)=593 (M+H)⁺.

[0355]¹H-NMR (300 MHz, DMSO-d₆) δ[ppm]: 0.82 (3H, t), 1.20-1.53 (4H, m),1.61-1.87 (4H, m), 2.56-2.69 (1H, m), 2.75-2.87 (1H, m), 3.05 (2H, q),3.13 (2H, t), 4.68 (2H, dd), 5.13-5.20 (1H, m), 6.79-6.87 (2H, m), 6.92(2H, t), 7.02-7.18 (9H, m), 7.63 (1H, br s), 8.05 (1H, d).

Example 2-18

[0356](1R,2R)-N-[(1S)-2-Amino-1-phenyl-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)-amino]carbonyl}(phenyl)amino]methyl}phenyl)cyclohexanecarboxamide:

[0357] a) N-Ethyl-N′-phenyl-N-(2-hydroxyethyl)urea:

[0358] At 0° C., a solution of 1.00 g (8.39 mmol) of phenyl isocyanatein 2 ml of dichloromethane is added dropwise to a solution of 820 mg(9.23 mmol) of N-ethylethanolamine in 4 ml of dichloromethane. After 10min at 0° C., the mixture is stirred at room temperature for 16 hours.The solution is concentrated under reduced pressure and the solidresidue is washed three times with in each case 20 ml of diethyl ether.This gives 1.71 g (98% of theory) of the product as a white solid.

[0359] R_(f) (dichloromethane/methanol 20:1)=0.17.

[0360] MS (ESI)=(208 M)⁺.

[0361]¹H-NMR (300 MHz, DMSO-d₆) δ[ppm]: 1.08 (3H, t), 3.28-3.39 (4H, m),3.57 (2H, q), 5.17 (1H, t), 6.91 (1H, t), 7.22 (2H, t), 7.39 (2H, d),8.44 (1H, br. s).

[0362] b)N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-N-ethyl-N′-phenylurea:

[0363] 1.70 ml (12.2 mmol) of triethylamine and a solution of 1.35 g(8.93 mmol) of TBDMS chloride in 5 ml of dichloromethane are added to asolution of 1.69 g (8.12 mmol) of the compound from Example 2-18a in amixture of 10 ml of dichloromethane and 3.0 ml abs. dimethylformamide.The mixture is stirred at room temperature for 18 hours and diluted with100 ml of diethyl ether. The mixture is washed three times with in eachcase 30 ml of water, dried with sodium sulphate and concentrated underreduced pressure. This gives 2.62 g (95% of theory) as a colourless oil.

[0364] R_(f) (dichloromethane/methanol 20:1)=0.67.

[0365] MS (ESI)=323 (M+H)⁺.

[0366]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.04 (6H, s), 0.85 (9H, s), 1.08(3H, t), 3.33-3.45 (4H, m), 3.72 (2H, t), 6.92 (1H, t), 7.22 (2H, t),7.42 (2H, d), 8.13 (1H, br. s).

[0367] c)tert-Butyl(1R,2R)-2-{4-[4-ethyl-2-phenyl-8,8,9,9-tetramethyl-3-oxo-7-oxa-2,4-diaza-8-siladec-1-yl]phenyl}cyclohexanecarboxylate:

[0368] A solution of 419 mg (1.30 mmol) of the compound from Example2-18b in 3 ml of DMF is added dropwise to a suspension of 54.6 mg (60%in mineral oil, 1.37 mmol) of sodium hydride in 1 ml of DMF. The mixtureis stirred at room temperature for 15 min, and a suspension of 535 mg(85.8%, 1.30 mmol) oftert-butyl(1R,2R)-2-(4-bromomethyl-phenyl)cyclohexane-1-carboxylate fromExample I in 4 ml of DMF is then added dropwise. The mixture is stirredat room temperature for 20 hours and then diluted with 50 ml of waterand extracted three times with in each case 30 ml of diethyl ether. Thecombined organic phases are washed with 100 ml of saturated sodiumchloride solution and dried over sodium sulphate. The crude product ispurified by column chromatography (silica gel (70-230 mesh),dichloromethane/ethanol 40:1). This gives 757 mg (91% of theory) of theproduct as a colourless oil.

[0369] R_(f) (petroleum ether/ethyl acetate 4:1)=0.57.

[0370] MS (ESI)=595 (M+H)⁺.

[0371]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.00 (6H, s), 0.80-0.85 (12H,m), 0.99 (9H, s), 1.20-1.52 (4H, m), 1.59-1.92 (4H, m), 2.32-2.61 (2H,m), 3.06 (2H, q), 3.15 (3H, t), 3.51 (2H, t), 4.67 (2H, s), 7.00-7.27(9H, m).

[0372] d)tert-Butyl(1R,2R)-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}-(phenyl)amino]methyl}phenyl)cyclohexanecarboxylate:

[0373] 350 μl (1.22 mmol) of a 1.1 M solution of tetra-n-butylammoniumfluoride in THF are added to a solution of 724 mg (1.22 mmol) of thecompound from Example 2-18c in 20 ml of THF. The mixture is stirred atroom temperature for 30 min and then diluted with 100 ml of diethylether. The mixture is washed three times with in each case 25 ml of asemisaturated sodium chloride solution and once with 20 ml of saturatedsodium chloride solution. The combined wash solutions are extracted with20 ml of diethyl ether and the combined organic phases are dried withsodium sulphate. Yield: 747 mg of a colourless oil (which still containstert-butyl(dimethyl)silyl fluoride). For characterization, a smallamount was purified by column chromatography (silica gel (70-230 mesh),gradient: from cyclohexane to cyclohexane/ethyl acetate 1:1).

[0374] R_(f) (cyclohexane/acetic acid 1:1)=0.4.

[0375] MS (ESI)=481 (M+H)⁺.

[0376]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.83 (3H, t), 1.00 (9H, s),1.20-1.52 (4H, m), 1.60-1.92 (4H, m), 2.35-2,61 (2H, m), 2.95-3.17 (4H,m), 3.29-3.43 (2H, m), 4.59 (1H, t), 4.68 (2H, s), 6.98-7.29 (9H, m).

[0377] e)(1R,2R)-2-(4-{[{[Ethyl(2-hydroxyethyl)amino]carbonyl}(phenyl)-amino]methyl}phenyl)cyclohexanecarboxylicAcid:

[0378] 724 mg (1.51 mmol) of the compound from Example 2-18d aredissolved in 2 ml of dichloromethane, and 1 ml of trifluoroacetic acidis added. The solution is stored at room temperature for 5 hours andthen treated with 15 ml of 1 N sodium hydroxide solution and 20 ml ofwater. The mixture is washed twice with in each case 20 ml of diethylether and adjusted to pH 3-4 using 1 N hydrochloric acid. The mixture isextractred three times with in each case 30 ml of dichloromethane andthe extracts are dried with sodium sulphate and concentrated. Theresidue is taken up in 4 ml of diethyl ether and re-concentrated. Theproduct, which is initially in oil, turns into a white solid foam.Yield: 276 mg (43% of theory, 99% purity according to HPLC).

[0379] R_(f) (dichloromethane/methanol 10:1)=0.35.

[0380] MS (ESI)=425 (M+H)⁺.

[0381]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.83 (3H, t), 1.20-1.55 (4H, m),1.59-1.82 (3H, m), 1.88-2.02 (1H, m), 2.40-2.72 (2H, m), 2.99-3.20 (4H,m), 3.25-3.50 (2H, m), 4.68 (2H, s), 7.00-7.32 (9H, m), 11.74 (1H, br.s)

[0382] f)(1R,2R)-N-[(1S)-2-Amino-1-phenyl-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(phenyl)amino]methyl}phenyl)cyclohexanecarboxamide:

[0383] 0.90 ml of abs. DMF is added to a mixture of 42.5 mg (0.100 mmol)of the compound from Example 2-18e, 13.5 mg (0.100 mmol) of HOBT, 23.0mg (0.120 mmol) of EDC and 1 mg of DMAP. The mixture is stirred at roomtemperature for 5 min until a clear solution has formed. 22.0 μl (20.2mg, 0.200 mmol) of N-methylmorpholine and 28 mg (0.150 mmol) ofL-phenylglycinamide hydrochloride are then added. The mixture is stirredat room temperature for 3 days and then separated directly using RP-HPLC(C18 Gromsil, 50×20 mm, 25 m/min, gradient water/acetonitrile90:10→water/acetonitrile 10:90 over 8 min). The acetonitrile is removedunder reduced pressure and the product precipitates in the form of whiteflakes. The product is frozen and lyophilized overnight. This gives 37.6mg (62% of theory) of the product as a white solid.

[0384] R_(f) (dichloromethane/methanol 10:1)=0.44.

[0385] MS (ESI)=557 (M+H)⁺.

[0386]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 0.84 (3H, t), 1.19-1.58 (4H, m),1.61-1.88 (4H, m), 2.56-2.90 (2H, m), 3.00-3.23 (4H, m), 3.25-3.50 (2H,m), 4.65 (1H, t), 4.72 (2H, s), 5.17 (1H, d), 6.79-6.87 (2H, m),6.95-7.30 (13H, m), 7.65 (1H, br s), 8.02 (1H, d).

[0387] The compounds listed in Table 2 below are prepared in ananalogous manner; in addition to the data given in the table, furtherspectroscopic data of the individual compounds are listed below:

[0388](S)-N-{{(1R,2R)-2-(4-{[{[Bis(2-hydroxyethyl)amino]carbonyl}(phenyl)amino]-methyl}phenyl)cyclohex-1-yl}carbonyl}-phenylglycinamide(Example 2-3)

[0389] MS (ESI)=573 (M+H)⁺.

[0390]¹H-NMR (200 MHz, DMSO-d₆) δ[ppm]: 1.21-1.60 (4H, in), 1.61-1.96(4H, m), 2.60-2.93 (2H, in), 3.19 (4H, t), 3.39 (4H, t), 4.76 (2H, s),5.15-5.25 (1H, m), 6.82-6.93 (2H, in), 6.90-7.35 (13H, in), 7.66 (1H,br. s), 8.04 (1H, d).

[0391](S)-N-{{(1R,2R)-2-(4-{[{[2-Hydroxylethylamino]carbonyl}(phenyl)amino]-methyl}phenyl)cyclohex-1-yl}carbonyl}-phenylglycinamide(Example 2-17)

[0392] MS (ESI)=551 (M+H)⁺.

[0393]¹H-NMR (300 MHz, DMSO-d₆) 6[ppM]: 1.20-1.55 (4H, in), 1.62-1.89(4H, m), 2.60-2.70 (1H, m), 2.77-2.86 (1H, m), 3.12 (2H, q) 3.32-3.40(2H, in), 4.59 (1H, t), 4.80 (1H, s), 5.17 (1H, d), 5.66 (1H, t),6.76-6.83 (2H, m), 6.97-7.23 (1H, in), 7.33 (2H, t), 7.65 (1H, br. s),8.02 (1H, d). TABLE 2 Example Structure Retention time (method) 2-2 

4.18 (A) 2-3 

3.97 (A) 2-4 

4.01 (A) 2-5 

3.89 (A) 2-6 

4.36 (A) 2-7 

4.17 (A) 2-8 

4.24 (A) 2-9 

4.29 (A) 2-10

4.12 (B) 2-11

4.36 (A) 2-12

3.98 (A) 2-13

4.03 (A) 2-14

3.90 (A) 2-15

4.00 (A) 2-16

3.90 (A) 2-17

3.92 (A)

Example 3-1

[0394]4-[(1R,2R)-2-({[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]amino}carbonyl)-cyclohexyl]benzyl4-hydroxy-1-piperidinecarbamate:

[0395] a)tert-Butyl(1R,2R)-2-{4-[(acetyloxy)methyl]phenyl}cyclohexanecarboxylate:

[0396] A suspension oftert-butyl(1R,2R)-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylatefrom Example I (3 g, 8.49 mmol), potassium acetate (1.83 g, 18.68 mmol)and 18-crown-6 (134.7 mg, 0.51 mmol) in acetonitrile (15 ml) is stirredat 50° C. for 24 hours and at 60° C. for a further 16 hours. Thereaction mixture is then concentrated under reduced pressure andextracted with water/methylene chloride. The organic phase is washedwith saturated sodium chloride solution and dried over sodium sulphate.Concentration of the crude product under reduced pressure and silica gelchromatography (mobile phase: cyclohexane/ethyl acetate=30:1 to 8:1)gives 2.7 g (95.6%) of product as a colourless solid.

[0397] MS (ESI+): 350.4 (M+NH₄)⁺

[0398]¹H-NMR (DMSO-d₆): 1.05 (9H, s); 1.30-1.55 (4H, m); 1.65-1.95 (4H,m); 2.02 (3H, s); 2.40-2.68 (2H, m); 5.02 (2H, s); 7.15-7.28 (4H, m).

[0399] b) (1R,2R)-2-{4-[(Acetyloxy)methyl]phenyl}cyclohexanecarboxylicAcid:

[0400] A solution of the compound from Example 3-1a (2.7 g, 8.12 mmol)in dichloromethane (15 ml) and trifluoroacetic acid (7.5 ml) is stirredat room temperature for 2 hours. The mixture is concentrated underreduced pressure and extracted with methylene chloride/water and thentwice with saturated sodium chloride solution, giving, afterconcentration of the organic phase under reduced pressure, 2.2 g (94%)of product as a solidified oil.

[0401] MS (ESI+): 294.3 (M+NH₄)⁺

[0402]¹H-NMR (DMSO-d₆): 1.30-1.55 (4H, m); 1.65-2.02 (4H, m); 2.03 (3H,s); 2.40-2.75 (2H, m); 5.00 (2H, s); 7.15-7.28 (4H, m); 11.71 (1H, s).

[0403] c)4-[(1R,2R)-2-({[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]amino}-carbonyl)cyclohexyl]benzylAcetate:

[0404] 1-Hydroxylbenzotriazole (1.18 g, 8.76 mmol) and EDC (1.60 g, 8.36mmol) are added to a solution of the compound from Example 3-1b (2.2 g,7.96 mmol) in DMF (80 ml), and the mixture is stirred at roomtemperature for 10 min. N-Methylmorpholine (3.50 ml, 31.85 mmol),(+)-(S)-4-fluorophenylglycinamide (1.63 g, 7.96 mmol) and a spatula tipof DMAP are then added, and the mixture is stirred at room temperatureovernight. Following addition of water (350 ml), the mixture is stirredat room temperature for 1 hour and then cooled with ice. The titlecompound is then filtered off, washed with water and diethyl ether anddried. Drying under reduced pressure (200 mbar, 50° C., 16 h) gives 2.70g (74.8%) of the product as a colourless solid.

[0405] MS (ESI+): 427.0 (M+H)⁺

[0406]¹H-NMR (DMSO-d₆): 1.25-1.55 (4H, m); 1.65-1.90 (4H, m); 2.06 (3H,s); 2.64-2.71 (1H, m); 2.80-2.90 (1H, m); 5.02 (2H, s); 5.20 (1H, d);6.75-6.94 (4H, m); 7.15-7.22 (5H, m); 7.67 (1H, s); 8.05 (1H, d).

[0407] d)(1R,2R)-N-[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]-2-[4-(hydroxymethyl)phenyl]cyclohexanecarboxamide:

[0408] A suspension of the compound from Example 3-1c (2.70 g, 6.61mmol) in ammonia solution (2M in methanol, 50 ml) is stirred at roomtemperature overnight. The mixture is concentrated under reducedpressure and the product is then stirred with diethyl ether (50 ml) for1 hour and then cooled with ice and filtered off. Drying under reducedpressure (200 mbar, 50° C., 16 h) gives the product as a colourlesssolid (2.50 g, 98.4%).

[0409] MS (ESI+): 385.5 (M+H)⁺

[0410]¹H-NMR (DMSO-d₆): 1.25-1.55 (4H, m); 1.65-1.88 (4H, m); 2.64-2.69(1H, m); 2.77-2.85 (1H, m); 4.45 (2H, s); 5.17 (1H, d); 6.70-6.76 (2H,m); 6.87-6.94 (2H, m); 7.10-7.17 (5H, m); 7.65 (1H, s); 7.98 (1H, d).

[0411] e)4-[(1R,2R)-2-({[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]amino}-carbonyl)cyclohexyl]benzyl4-hydroxy-1-piperidinecarbamate:

[0412] Triethylamine (0.16 ml, 1.17 mmol) and disuccinimidyl carbonate(149.9 mg, 0.59 mmol) are added to a solution of the compound fromExample 3-1d (150.0 mg, 0.39 mmol) in DMF (5 ml), and the mixture isstirred at room temperature for 5 hours. 4-Hydroxylpiperidine (157.8 mg,1.56 mmol) is then added, and the mixture is stirred at room temperaturefor 12 hours. After filtration, the solution is separated directly bypreparative HPLC (column: Kroniasil 100 C 18.5 μm, 250×40 mm; mobilephase: methanol/water; flow rate: 25 ml/min; UV detection at 210 nm).Following concentration under reduced pressure, 93.7 mg (45.6%) of theproduct are obtained as a colourless solid.

[0413] MS (ESI+): 534.2 (M+Na)⁺

[0414]¹H-NMR (DMSO-d₆): 1.15-1.95 (12H, m); 2.55-2.95 (2H, m); 2.95-3.16(2H, m); 3.55-3.80 (3H, m); 4.72 (1H, d); 5.02 (2H, s); 5.19 (1H, d);6.70-6.95 (4H, m); 7.10-7.25 (5H, m); 7.70 (1H, br.s); 8.09 (1H, d).

Example 3-23

[0415]4-[(1R,2R)-2-({[(1S)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]amino}carbonyl)-cyclohexyl]benzyl4-(2-hydroxyethyl)-1-piperazinecarbamate:

[0416] Triethylamine (0.06 ml, 0.43 mmol) and disuccinimidyl carbonate(73.3 mg, 0.29 mmol) are added to a solution of the compound fromExample 3-1d (55 mg, 0.14 mmol) in DMF (2 ml), and the mixture isstirred at room temperature overnight. The reaction mixture is admixedwith methylene chloride (about 10 ml) and washed 3× with a littlesaturated ammonium chloride solution. The organic phase is then driedover sodium sulphate and, after filtration, concentrated under reducedpressure. The resulting crude mixture is added to a mixture ofN-(2-hydroxylethyl)piperazine (74.3 mg, 0.57 mmol) and a spatiila tip ofDMAP and stirred at room temperature for 12 hours. Following filtration,the solution is separated directly by preparative HPLC (column: Kromasil100 C 18.5 μm, 250×40 mm; mobile phase: acetonitrile/water; flow rate:25 m/min; UV detection at 210 nm). Following concentration under reducedpressure, 25 mg (29.8%) of the product are obtained as a colourlesssolid.

[0417] MS (ESI+): 541.3 (M+H)⁺

[0418]¹H-NMR (DMSO-d₆): 1.20-1.60 (4H, m); 1.65-1.90 (4H, m); 2.25-2.60(8H, m); 2.60-2.90 (2H, m); 3.25-3.54 (4H, m); 4.38 (1H, t); 5.03 (2H,s); 5.19 (1H, d); 6.72-6.95 (4H, m); 7.08-7.24 (5H, m); 7.62 (1H, s);8.02 (1H, d).

Example 3-36

[0419]4-[(1R,2R)-2-({[(1S)-2-Amino-1-phenyl-2-oxoethyl]amino}carbonyl)-cyclohexyl]benzyl4-(2-hydroxyethyl)-1-piperazinecarbamate:

[0420] is prepared analogously to Example 3-23 using, instead of(+)-(S)-4-fluorophenylglycinamide, (+)-(S)-phenylglycinamide.Purification is carried out by preparation HPLC (column: Waters SymmetryC 18, 7 μm, 300×19 mm; mobile phase: acetonitrile/water/2% acetic acid,flow rate: 25 ml/min; UV detection at 230 nm). Following concentrationunder reduced pressure, the product is obtained in the form of theacetate, from which, by addition of methylene chloride and subsequentextraction with a 1:1 mixture of saturated sodium chloride solution and2 molar sodium carbonate solution, the compound is obtained as acolourless solid.

[0421] MS (ESI+): 523 [M+H]⁺

[0422]¹H-NMR (DMSO-d₆): 1.20-1.60 (4H, m); 1.65-1.92 (4H, m); 2.27-2.60(8H, m); 2.60-2.95 (2H, m); 3.27-3.55 (4H, m); 4.41 (1H, t); 5.03 (2H,s); 5.19 (1H, d); 6.70-6.85 (2H, m); 7.0-7.26 (8H, m); 7.66 (1H, s);8.02 (1H, d).

[0423] The compounds listed in Table 3 below are prepared in ananalogous manner: TABLE 3 Example Structure Retention time (method) 3-2 

4.02 (C) 3-3 

4.00 (C) 3-4 

3.73 (C) 3-5 

2.54 (C) 3-6 

4.39 (C) 3-7 

4.42 (C) 3-8 

3.86 (C) 3-9 

4.38 (C) 3-10

4.47 (C) 3-11

4.04 (C) 3-12

4.08 (C) 3-13

2.58 (C) 3-14

3.80 (C) 3-15

3.91 (C) 3-16

4.14 (C) 3-17

3.54 (C) 3-18

3.19 (C) 3-19

2.45 (C) 3-20

3.56 (C) 3-21

3.82 (C) 3-22

2.51 (C) 3-23

3.66 (A) 3-24

3.57 (A) 3-25

3.68 (A) 3-26

3.64 (A) 3-27

3.77 (A) 3-28

3.86 (A) 3-29

2.64 (C) 3-30

2.40 (C) 3-31

2.63 (C) 3-32

3.71 (E) 3-33

4.35 (E) 3-34

4.00 (E) 3-35

Rf (CH2Cl2:MeOH =20:1) 0.35

Example 4-1

[0424] Benzyl(4-[2-({[(1S)-2-amino-2-oxo-1-phenylethyl]amino}carbonyl)cyclohexyl]-benzyl)-carbamate:

[0425] a) tert-Butyl2-[4-({bis[(benzyloxy)carbonyl]amino}methyl)phenyl]cyclohexancarboxylate:

[0426] is obtained analogously to the general procedure A from racemictert-butyl trans-2-(4-bromomethylphenyl)-cyclohexane-1-carboxylateaccording to Example I and bis[(benzyloxy)carbonyl]amine (U. Ragnarssonet al., Synthesis, 1988, 992) in the presence of NaH in DMF.

[0427] b)2-[4-({(Benzyloxy)carbonylamino}methyl)phenyl]cyclohexanecarboxylicAcid:

[0428] The ester from Example 4-1a (0.36 mmol) is dissolved indichloromethane (5 ml), treated with trifluoroacetic acid (5 ml) andstirred at room temperature for 2 hours. For work-up, the mixture is, at0° C., neutralized with 2M aqueous sodium hydroxide solution andextracted with dichloromethane, and the organic phase is dried overmagnesium sulphate and concentrated. The residue is chromatographed(silica gel; cyclohexane:ethyl acetate:acetic acid 3:1:0.1), giving 91.2mg of acid.

[0429] R_(f) (cyclohexane:ethyl acetate:acetic acid 3:1:0.2)=0.21

[0430] c) Benzyl4-[2-({[(1S)-2-amino-2-oxo-1-phenylethyl]amino}carbonyl)cyclohexyl]benzyl)carbamate:

[0431] is prepared analogously to the general procedure C from the acidaccording to Example 4-1b and (S)-phenylglycinamide hydrochloride. Amixture of the trans diastereomers is obtained.

[0432] R_(f) (methylene chloride/methanol 20:1)=0.32.

Example 5-1

[0433]N-{4-[2-({[(1S)-2-Amino-2-oxo-1-phenylethyl]amino}carbonyl)cyclohexyl]-benzyl}4-fluorobenzamide:

[0434] a) tert-Butyl2-{4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-cyclohexanecarboxylate:

[0435] Racemic tert-butyltrans-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylate according toExample 1 (6.3 mmol) is initially charged in DMF (30 ml) and treatedwith potassium phthalimide (6 mmol). After 5 min at room temperature,the mixture is heated at 50° C. for 20 hours. Following addition ofwater, extraction with ether and flash chromatography on silica gel(dichloromethane:cyclohexane 1:1→dichloromethane), 1.66 g of a slightlyyellowish solid are obtained.

[0436] R_(f) (methylene chloride)=0.2

[0437] b)-c) The Hydrolysis of the Ester and the Subsequent AmideFormation are Carried Out Analogously to the General Procedures B and C

[0438] d)(2S)-N-[2-(4-Aminomethyl-phenyl)-cyclohexyl-1-carbonyl]-phenylglycinamide:

[0439] Hydrazine hydrate (7.6 mmol) is added to a suspension of thephthalimide from Example 5-1c (0.5 mmol) in ethanol (10 ml), and themixture is stirred at room temperature for 3 days. 1 M HCl is addeduntil a pH=2 is reached, and the mixture is then partitioned betweendichloromethane and 10% strength sodium bicarbonate solution and theorganic phase is dried over sodium sulphate and concentrated.Chromatography (silica gel, dichloromethane:methanol:ammonia 100:10:1)gives 105 mg (51% yield) of a mixture of diastereomers as a yellowishsolid.

[0440] R_(f) (dichloromethane:methanol:ammonia 100:10:1)=0.13 and 0.10

[0441] MS (DCI, NH₃)=510 (M+H⁺).

[0442]¹H-NMR (DMSO-d₆): A: 1.25-1.4 (4H, m);); 1.7-1.85 (4H, m);2.55-2.8 (2H, m); 3.3 (2H, br s); 3.7 (2H, s); 5.1 (1H, d); 6.85 (1H,s); 6.95 (1H, s); 7.1-7.3 (9H, m); 8.15 (1H, d); B: 1.35-1.55 (4H, m););1.65-1.9 (4H, m); 2.2 (2H, br s); 2.6-2.7 (1H, m); 2.8 (1H, td); 3.7(2H, s); 5.2 (1H, d); 6.85 (2H, d); 7.05-7.2 (8H, m); 7.6 (1H, s); 7.95(1H, d).

[0443] e)N-{4-[2-({[(1S)-2-Amino-2-oxo-1-phenylethyl]amino}carbonyl)-cyclohexyl]benzyl}4-fluorobenzamide:

[0444] The amine from Example 5-1d (0.274 mmol) is, together withtriethylamine (0.82 mmol), dissolved in dichloromethane (3 ml) andtreated with 4-fluorobenzoic anhydride (0.3 mmol). The mixture isstirred at room temperature until its consistency is gel-like (about 5min). Methanol is then added until the mixture is completely dissolved,the solution is then adsorbed on silica gel and the product is elutedusing dichloromethane/methanol 10:1. This gives 101 mg of the desiredproduct.

[0445] R_(f) (dichloromethane:methanol 10:1)=0.24

[0446] The compounds listed in Table 4 below are prepared in ananalogous manner: TABLE 4 R_(f) value Example Structure (CH₂Cl₂:MeOH:NH₃aq) 5-2

0.22 (10:1:0) 5-3

0.38 (10:1:0) 5-4

0.42/0.4 (10:1:0)

Example 6-1

[0447](1R,2R)-N-[(1R)-2-Amino-1-(4-fluorophenyl)-2-oxoethyl]-2-{4-[3-(cyclopropylamino)-3-oxopropyl]phenyl}cyclohexanecarboxamide:

[0448] a) Dimethyl2-{4-[(1R,2R)-2-(tert-butoxycarbonyl)cyclohexyl]benzyl}-malonate:

[0449] Dimethyl malonate (1.86 ml, 16.28 mmol) is added to a suspensionof NaH (60% in mineral oil, 0.62 g, 15.57 mmol) in THF (50 ml), and themixture is stirred at room temperature for 15 min. The resultingsolution is added to a solution of tert-butyl(1R,2R)-2-(4-bromomethyl-phenyl)-cyclohexane-1-carboxylate from ExampleI (5 g, 14.15 mmol) in THF (50 ml), and the mixture is stirred overnightat room temperature. The mixture is then admixed with water (200 ml) andethyl acetate (500 ml) and shaken, and the organic phase is washed withsaturated ammonium chloride solution and sodium chloride solution. Theorganic phase is dried over sodium sulphate, filtered, concentratedunder reduced pressure and chromatographed on silica gel (mobile phase:cyclohexane/ethyl acetate=6:1), giving 5 g (87%) of product as acolourless liquid.

[0450] MS (DCI): 422.4 (M+NH₄)⁺

[0451]¹H-NMR (DMSO-d₆): 1.15 (9H, s); 1.30-1.50 (4H, m); 1.65-1.95 (4H,m); 2.35-2.65 (2H, m); 3.03 (2H, d); 3.60 (6H, s); 3.81 (1H, t);6.95-7.15 (4H, m).

[0452] b)(1R,2R)-2-{4-[3-Methoxy-2-(methoxycarbonyl)oxopropyl]phenyl}cyclohexanecarboxylicAcid:

[0453] Under ice-cooling, trifluoroacetic acid (57.2 ml) is added to asolution of the compound from Example 6-1a (5 g, 12.36 mmol) indichloromethane (130.7 ml), and the mixture is then stirred at roomtemperature for 5 hours. Concentration of the mixture under reducedpressure and silica gel chromatography (mobile phase:dichloromethane/methanol=60:1 to 20:1) gives 3.2 g (74%) of product as acolourless foam.

[0454] MS (DCI): 366.1 (M+NH₄)⁺

[0455]¹H-NMR (DMSO-d₆): 1.30-1.50 (4H, m); 1.65-1.70 (3H, m); 1.90-2.00(1H, m); 2.45-2.55 (1H, m); 2.60-2.70 (1H, m); 3.03 (2H, d); 3.60 (6H, 2s); 3.83 (1H, t); 7.10 (4H, q).

[0456] c) Dimethyl2-{4-[(1R,2R)-2-({[(1S)-2-amino-1-(4-fluorophenyl)-2-oxoethyl]amino}carbonyl)cyclohexyl]benzyl}malonate:

[0457] 1-Hydroxylbenzotriazole (0.38 g, 2.80 mmol) and EDC (0.56 g, 2.92mmol) are added to a solution of the compound from Example 6-1b (0.89 g,2.54 mmol) in DMF (20 ml), and the mixture is stirred at roomtemperature for 10 min. N-Methylmorpholine (1.40 ml, 12.72 mmol),(+)-(S)-4-fluorophenylglycinamide (0.52 g, 2.54 mmol) and a spatula tipof DMAP are then added, and the mixture is stirred at room temperatureovernight. Following addition of water (50 ml), the mixture is stirredat room temperature for 1 hour. The title compound is then filtered off,washed with water and diethyl ether and dried. This gives 1.17 g (92%)of a colourless solid.

[0458] MS (ESI+): 499.3 (M+H⁺)

[0459]¹H-NMR (DMSO-d₆): 1.20-1.90 (8H, m); 2.55-2.90 (2H, m); 3.03 (2H,d); 3.60 (6H, 2 s); 3.81 (1H, t); 5.16 (1H, d); 6.80-7.20 (9H, m); 7.64(1H, br.s); 8.08 (1H, d).

[0460] d)3-{4-[(1R,2R)-2-({[2-Amino-1-(4-fluorophenyl)-2-oxoethyl]amino}-carbonyl)cyclohexyl]phenyl}propanecarboxylicAcid (Mixture of Epimers or R,R,R-diastereomer)

[0461] Lithium hydroxide (0.28 g, 11.73 mmol) is added to a suspensionof the compound from Example 6-1c (1.17 g, 2.35 mmol) in methanol (10ml) and water (40 ml), and the mixture is stirred at 50° C. for 1 hour.The methanol is then distilled off, and the mixture is acidified with 2N hydrochloric acid to pH 2. The resulting residue is extracted withmethylene chloride/methanol and concentrated under reduced pressure. Theresidue is then taken up in dioxane (100 ml) and at 120° C. refluxedovernight. Concentration under reduced pressure gives 508 mg (50.5%) ofthe product (mixtures of epimers) as a colourless oil. When a littlemethylene chloride/methanol is added to this oil, the pure(R,R,R)-diastereomer (102 mg, 13%) crystallizes from the solution as acolourless solid.

[0462] MS (mixture of epimers, ESI+): 427.3 (M+H)⁺

[0463]¹H-NMR [R,R,R-diastereomer] (DMSO-d₆): 1.20-1.45 (4H, m);1.60-1.90 (4H, m); 2.45-2.60 (obscured by the DMSO signal); 2.60-2.90(4H, m); 5.12 (1H, d); 6.80-7.35 (10H, m); 8.18 (1H, d); 12.15 (1H,br.s).

[0464] e)(1R,2R)-N-[2-amino-1-(4-fluorophenyl)-2-oxoethyl]-2-{4-[3-(cyclopropylamino)-3-oxopropyl]phenyl}cyclohexanecarboxamide(R,R,R-diastereomer or R,R,S-diastereomer):

[0465] 1-Hydroxylbenzotriazole (8.7 mg, 0.064 mmol) and EDC (12.9 mg,0.067 mmol) are added to a solution of the compound from Example 6-1d(R,R,R-diastereomer, 25.0 mg, 0.059 mmol) in DMF (1.5 ml), and themixture is stirred at room temperature for 10 min. N-Methylmorpholine(0.016 ml, 0.147 mmol), cyclopropylamine (8.4 mg, 0.147 mmol) and aspatula tip of DMAP are then added and the mixture is stirred at roomtemperature overnight. Following concentration of the mixture underreduced pressure, the crude product is taken up in methylene chloride,washed with water and dried over sodium sulphate. The crude product isconcentrated under reduced pressure and chromatographed on silica gel(mobile phase: dichloromethane/methanol=20:1 to 10:1), giving 25.0 mg(92%) of product as a colourless solid.

[0466] MS (ESI+): 466.3 (M+H)⁺

[0467]¹H-NMR (DMSO-d₆): 0.30-0.65 (4H, m); 1.20-1.40 (4H, m); 1.65-1.80(4H, m); 2.25-2.35 (2H, m); 2.45-2.80 (5H, m); 5.16 (1H, d); 6.90-7.35(10H, m); 7.85 (1H, d); 8.15 (1H, d).

[0468] The corresponding (R,R,S)-diastereomer can be preparedanalogously by using the compound from Example 6-1d (mixture of epimers)as starting material. Here, the product is obtained as a mixture ofepimers which can be separated into the pure epimers [(R,R,S)— and(R,R,R)-diastereomers] by preparative HPLC chromatography (column:Kromasil 100 C 18, 5 μm, 50×20 mm; mobile phase: acetonitrile/water;flow rate: 10 ml/min; UV detection at 254 nm).

Example 6-2

[0469](1R,2R)-N-[2-Amino-1-(4-fluorophenyl)-2-oxoethyl]-2-(4-{3-[bis(2-methoxyethyl)amino]-3-oxopropyl}phenyl)cyclohexanecarboxamide

[0470](1R,2R)-N-[2-Amino-1-(4-fluorophenyl)-2-oxoethyl]-2-(4-{3-[bis(2-methoxyethyl)-amino]-3-oxopropyl}phenyl)cyclohexanecarboxamideis prepared analogously to the reaction sequence described in Example6-1.

[0471] Rt time (method C)=3.57

[0472] The HPLC retention times given in the examples and tables aboverefer to the HPLC methods below

[0473] A: Mobile phase A:=1% HClO₄ in water, B=acetonitrile, gradient:0.5 min 98% A, 4.5 min 10% A, 6.5 min 10% A, 6.7 min 98% A, 7.5 min 98%A, Kromasil 100 C18, 60×2 mm, 0.75 m/min, 210 nm, 30° C.

[0474] B: Mobile phase A:=1% HClO₄ in water, B=acetonitrile, gradient:0.5 min 98% A, 4.5 min 10% A, 9.0 min 10% A, 9.2 min 98% A, 10.0 min 98%A, Kromasil 100 C18, 60×2 mm, 0.75 ml/min, 210 nm, 30° C.

[0475] C: Mobile phase A:=0.1% formic acid in water, B=0.1% formic acidin acetonitrile, gradient: 0 min 90% A, 4 min 10% A, 6.1 min 90% A,symmetry C18, 50×2.1 mm, 0.5 m/min, 210 nm, 30° C.

[0476] D: Mobile phase A:=0.01 M phosphoric acid in water,B=acetonitrile, gradient: 1 min 90% A, 9 min 10% A, 13 min 10% A, 13.5min 90% A, 15 min, 90% A, Kromasil 100 C18, 125×2 mm, 210 nm, 30° C.

[0477] E: Mobile phase A:=0.5% HClO₄ in water, B=acetonitrile, gradient:0.5 min 98% A, 4.5 min 10% A, 6.5 min 10% A, 6.7 min 98% A, 7.5 min 98%A, Kromasil 100 C18, 60×2 mm, 0.75 ml/min, 210 nm, 30° C.

1. Compounds of the formula (I)

in which D represents a radical

in which R² represents hydrogen, halogen, hydroxyl, carboxyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxyor (C₁-C₆)-alkoxycarbonyl, A represents an oxygen atom or a group of theformula N—R⁵ or CH—R⁶, in which R⁵ represents hydrogen, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, where alkyl and cycloalkyl for their part may besubstituted up to three times independently of one another by hydroxylor mono- or di-(C₁-C₆)-alkylamino, represents (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S or 5- or 6-membered heterocyclyl having up tothree heteroatoms from the group consisting of N, O and S, where aryl,heteroaryl and heterocyclyl for their part may be substituted up tothree times independently of one another by halogen, hydroxyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₁-C₆)-alkyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl or mono- or di-(C₁-C₆)-alkylamino, R⁶ representshydrogen, (C₁-C₆)-alkoxycarbonyl or carboxyl, R¹ represents hydrogen,(C₁-C₆)-alkyl, which for its part may be substituted by hydroxyl or(C₁-C₄)-alkoxy, represents (C₃-C₇)-cycloalkyl, (C₆-C₁₀)-aryl, 5- to10-membered heteroaryl having up to two heteroatoms from the groupconsisting of N, O and S, where aryl and heteroaryl for their part maybe substituted independently of one another by halogen, or represents aradical of the formula —NR⁷R⁸ or —OR⁹, in which R⁷ and R⁸ independentlyof one another represent hydrogen, (C₆-C₁₀)-aryl, adamantyl,(C₁-C₈)-alkyl, whose chain may be interrupted by one or two oxygen atomsand which may be substituted up to three times independently of oneanother by hydroxyl, phenyl, trifluoromethyl, (C₃-C₈)-cycloalkyl,(C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, 5- or 6-memberedheterocyclyl having up to three heteroatoms from the group consisting ofN, O and S or by 5- to 10-membered heteroaryl having up to threeheteroatoms from the group consisting of N, O and S, represent(C₃-C₈)-cycloalkyl, which may be substituted up to three timesindependently of one another by (C₁-C₄)-alkyl, hydroxyl or oxo, orrepresent 5- or 6-membered heterocyclyl having up to two heteroatomsfrom the group consisting of N, O and S, where N is substituted byhydrogen or (C₁-C₄)-alkyl, or R⁷ and R⁸ together with the nitrogen atomto which they are attached form a 4- to 7-membered saturated heterocyclewhich may contain up to two further heteroatoms from the groupconsisting of N, O and S and which is optionally substituted byhydroxyl, oxo or (C₁-C₆)-alkyl, which for its part may be substituted byhydroxyl, and R⁹ represents (C₆-C₁₀)-aryl, adamantyl, (C₁-C₈)-alkyl,whose chain may be interrupted by one or two oxygen atoms and which maybe substituted up to three times independently of one another byhydroxyl, phenyl, trifluoroomethyl, (C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy,mono- or di-(C₁-C₆)-alkylamino, 5- or 6-membered heterocyclyl having upto three heteroatoms from the group consisting of N, O and S or by 5- to10-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S, represents (C₃-C₈)-cycloalkyl, which may besubstituted up to three times independently of one another by(C₁-C₄)-alkyl, hydroxyl or oxo, or represents 5- or 6-memberedheterocyclyl having up to two heteroatoms from the group consisting ofN, O and S, where N is substituted by hydrogen or (C₁-C₄)-alkyl, R³represents (C₁-C₈)-alkyl, whose chain may be interrupted by a sulphur oroxygen atom or an S(O) or SO₂ group, represents phenyl, benzyl or 5- or6-membered heteroaryl having up to two heteroatoms from the groupconsisting of N, O and S, where phenyl, benzyl and heteroaryl may besubstituted up to three times independently of one another by halogen,trifluoroomethyl, cyano, nitro, hydroxyl, (C₁-C₆)-alkyl or(C₁-C₆)-alkoxy, and R⁴ represents a radical of the formula—C(O)—NR¹⁰R¹¹, in which R¹⁰ and R¹¹ independently of one anotherrepresent hydrogen or (C₁-C₆)-alkyl, and their salts, hydrates, hydratesof the salts and solvates.
 2. Compounds according to claim 1, in which Drepresents a radical

in which R² represents hydrogen, halogen, hydroxyl, carboxyl, cyano,nitro, trifluoroomethyl, trifluoroomethoxy, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy or (C₁-C₆)-alkoxycarbonyl, A represents an oxygen atom ora group of the formula N—R⁵ or CH—R⁶, in which R⁵ represents hydrogen,(C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, where alkyl and cycloalkyl for theirpart may be substituted up to three times independently of one anotherby hydroxyl or mono- or di-(C₁-C₆)-alkylamino, represents (C₆-C₁₀)-aryl,5- to 10-membered heteroaryl having up to three heteroatoms from thegroup consisting of N, O and S or 5- or 6-membered heterocyclyl havingup to three heteroatoms from the group consisting of N, O and S, wherearyl, heteroaryl and heterocyclyl for their part may be substituted upto three times independently of one another by halogen, hydroxyl, cyano,nitro, trifluoroomethyl, trifluoroomethoxy, (C₁-C₆)-alkyl,(C₁-C₆)-alkoxy, (C₁-C₆)-alkoxycarbonyl or mono- ordi-(C₁-C₆)-alkylamino, R⁶ represents hydrogen, (C₁-C₆)-alkoxycarbonyl orcarboxyl, R¹ represents hydrogen, (C₁-C₆)-alkyl, which for its part maybe substituted by hydroxyl or (C₁-C₄)-alkoxy, represents(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-aryl, 5- to 10-membered heteroaryl havingup to two heteroatoms from the group consisting of N, O and S, wherearyl and heteroaryl for their part may be substituted independently ofone another by halogen, or represents a radical of the formula —NR⁷R⁸ or—OR⁹, in which R⁷ and R⁸ independently of one another representhydrogen, (C₆-C₁₀)-aryl, adamantyl, (C₁-C₈)-alkyl, whose chain may beinterrupted by one or two oxygen atoms and which may be substituted upto three times independently of one another by hydroxyl, phenyl,trifluoroomethyl, (C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, mono- ordi-(C₁-C₆)-alkylamino, 5- or 6-membered heterocyclyl having up to threeheteroatoms from the group consisting of N, O and S or by 5- to10-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S, represent (C₃-C₈)-cycloalkyl, which may besubstituted up to three times independently of one another by(C₁-C₄)-alkyl, hydroxyl or oxo, or represent 5- or 6-memberedheterocyclyl having up to two heteroatoms from the group consisting ofN, O and S, where N is substituted by hydrogen or (C₁-C₄)-alkyl, or R⁷and R⁸ together with the nitrogen atom to which they are attached form a4- to 7-membered saturated heterocycle which may contain up to twoheteroatoms from the group consisting of N, O and S and which isoptionally substituted by hydroxyl, oxo or (C₁-C₆)-alkyl, which for itspart may be substituted by hydroxyl, and R⁹ represents (C₆-C₁₀)-aryl,adamantyl, (C₁-C₈)-alkyl, whose chain may be interrupted by one or twooxygen atoms and which may be substituted up to three timesindependently of one another by hydroxyl, phenyl, trifluoroomethyl,(C₃-C₈)-cycloalkyl, (C₁-C₆)-alkoxy, mono- or di-(C₁-C₆)-alkylamino, 5-or 6-membered heterocyclyl having up to three heteroatoms from the groupconsisting of N, O and S or by 5- to 10-membered heteroaryl having up tothree heteroatoms from the group consisting of N, O and S, represents(C₃-C₈)-cycloalkyl, which may be substituted up to three timesindependently of one another by (C₁-C₄)-alkyl, hydroxyl or oxo, orrepresents 5- or 6-membered heterocyclyl having up to two heteroatomsfrom the group consisting of N, O and/or S, where N is substituted byhydrogen or (C₁-C₄)-alkyl, R³ represents (C₁-C₈)-alkyl, whose chain maybe interrupted by a sulphur atom or an S(O) or SO₂ group, representsphenyl, benzyl or 5- or 6-membered heteroaryl having up to twoheteroatoms from the group consisting of N, O and S, where phenyl,benzyl and heteroaryl may be substituted up to three times independentlyof one another by halogen, trifluoroomethyl, cyano, nitro, hydroxyl,(C₁-C₆)-alkyl or (C₁-C₆)-alkoxy, and R⁴ represents a radical of theformula —C(O)—NR¹⁰R¹¹, in which R¹⁰ and R¹¹ independently of one anotherrepresent hydrogen or (C₁-C₆)-alkyl, and their salts, hydrates, hydratesof the salts and solvates.
 3. Compounds according to claim 1, in which Drepresents a radical

in which R² represents hydrogen, chlorine or fluorine, A represents anoxygen atom or a group of the formula N—R⁵, in which R⁵ representshydrogen, (C₁-C₆)-alkyl, which for its part may be substituted up to twotimes by hydroxyl, represents (C₃-C₇)-cycloalkyl, phenyl or 5- or6-membered heteroaryl having up to three heteroatoms from the groupconsisting of N, O and S, where phenyl and heteroaryl for their part maybe substituted up to two times independently of one another by halogen,cyano, trifluoroomethyl, trifluoroomethoxy, (C₁-C₄)-alkyl,(C₁-C₄)-alkoxy or di-(C₁-C₄)-alkylamino, R¹ represents hydrogen,(C₁-C₆)-alkyl, which for its part may be substituted by hydroxyl or(C₁-C₄)-alkoxy, represents (C₃-C₇)-cycloalkyl, phenyl, 5- or 6-memberedheteroaryl having up to two heteroatoms from the group consisting of N,O and S, where phenyl and heteroaryl for their part independently may besubstituted independently of one another by halogen, or represents aradical of the formula —NR⁷R⁸ or —OR⁹, in which R⁷ and R⁸ independentlyof one another represent hydrogen, phenyl, adamantyl, (C₁-C₆)-alkyl,whose chain may be interrupted by one or two oxygen atoms and which maybe substituted up to two times independently of one another by hydroxyl,phenyl, trifluoroomethyl, (C₃-C₆)-cycloalkyl, (C₁-C₄)-alkoxy, mono- ordi-(C₁-C₄)-alkylamino, 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N and O or by 5- or 6-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and S, represents (C₃-C₈)-cycloalkyl, which may be substituted upto two times by hydroxyl, or represent 5- or 6-membered heterocyclylhaving up to two heteroatoms from the group consisting of N, O and S,where N is substituted by hydrogen or (C₁-C₄)-alkyl, or R⁷ and R⁸together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocycle which may contain up to two furtherheteroatoms from the group consisting of N, O and S and which isoptionally substituted by by hydroxyl, oxo or (C₁-C₆)-alkyl, which forits part may be substituted by hydroxyl, and R⁹ represents phenyl,adamantyl, (C₁-C₆)-alkyl, whose chain may be interrupted by one or twooxygen atoms and which may be substituted up to two times independentlyof one another by hydroxyl, phenyl, trifluoroomethyl,(C₃-C₆)-cycloalkyl, (C₁-C₃)-alkoxy, mono- or di-(C₁-C₄)-alkylamino, 5-or 6-membered heterocyclyl having up to two heteroatoms from the groupconsisting of N and O or by 5- or 6-membered heteroaryl having up tothree heteroatoms from the group consisting of N, O and S, represents(C₃-C₈)-cycloalkyl, which may be substituted up to two times byhydroxyl, or represents 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N, O and S, where N issubstituted by hydrogen or (C₁-C₄)-alkyl, R³ represents (C₁-C₈)-alkyl,whose chain may be interrupted by a sulphur atom or an S(O) or SO₂group, represents phenyl, benzyl or 5- or 6-membered heteroaryl havingup to two heteroatoms from the group consisting of N, O and S, wherephenyl, benzyl and heteroaryl may be substituted up to two timesindependently of one another by halogen, trifluoroomethyl, cyano,(C₁-C₃)-alkyl, (C₁-C₃)-alkoxy or hydroxyl, and R⁴ represents a radicalof the formula —C(O)—NR¹⁰R¹¹, in which R¹⁰ and R¹¹ independently of oneanother represent hydrogen or (C₁-C₆)-alkyl, and their salts, hydrates,hydrates of the salts and solvates.
 4. Compounds according to claim 1,in which D represents a radical of the formula

in which R² represents hydrogen, A represents an oxygen atom or a groupof the formula N—R⁵, in which R⁵ represents hydrogen, (C₁-C₆)-alkyl,which for its part may be substituted up to two times by hydroxyl,represents (C₃-C₇)-cycloalkyl, phenyl or 5- or 6-membered heteroarylhaving up to three heteroatoms from the group consisting of N, O and S,where phenyl and heteroaryl for their part may be substituted up to twotimes independently of one another by fluorine, chlorine, cyano,trifluoroomethyl, trifluoroomethoxy, (C₁-C₃)-alkyl, (C₁-C₃)-alkoxy ordi-(C₁-C₃)-alkylamino, R¹ represents (C₁-C₄)-alkyl or a radical of theformula —NR⁷R⁸, in which R⁷ and R⁸ independently of one anotherrepresent hydrogen, phenyl, adamantyl, (C₁-C₄)-alkyl, whose chain may beinterrupted by one or two oxygen atoms and which may be substituted upto two times independently of one another by hydroxyl, phenyl,trifluoroomethyl, (C₃-C₆)-cycloalkyl, (C₁-C₃)-alkoxy, mono- ordi-(C₁-C₃)-alkylamino, 5- or 6-membered heterocyclyl having up to twoheteroatoms from the group consisting of N and O or by 5- or 6-memberedheteroaryl having up to three heteroatoms from the group consisting ofN, O and S, represent (C₃-C₈)-cycloalkyl, which may be substituted uptwo times by hydroxyl, or represents 5- or 6-membered heterocyclylhaving up to two heteroatoms from the group consisting of N, O and S,where N is substituted by hydrogen or (C₁-C₄)-alkyl, or R⁷ and R⁸together with the nitrogen atom to which they are attached form a 4- to7-membered saturated heterocycle which may contain up to two furtherheteroatoms from the group consisting of N, O and S and which isoptionally substituted by by hydroxyl, oxo or (C₁-C₆)-alkyl, which forits part may be substituted by hydroxyl, R³ represents (C₁-C₈)-alkyl,whose chain may be interrupted by a sulphur atom or an S(O) or SO₂group, represents phenyl, benzyl or 5- or 6-membered heteroaryl havingup to two heteroatoms from the group consisting of N, O and S, wherephenyl, benzyl and heteroaryl may be substituted up to two timesindependently of one another by halogen, trifluoroomethyl, cyano,(C₁-C₃)-alkyl, (C₁-C₃)-alkoxy or hydroxyl, and R⁴ represents a radicalof the formula —C(O)—NR¹⁰R¹¹, in which R¹⁰ and R¹¹ independently of oneanother represent hydrogen, methyl or ethyl, and their salts, hydrates,hydrates of the salts and solvates.
 5. Compounds according to claim 1,in which D represents a radical

in which R² represents hydrogen, A represents an oxygen atom or a groupof the formula N—R⁵, in which R⁵ represents (C₃-C₇)-cycloalkyl, phenyl,which for its part may be substituted by fluorine, or representspyridyl, R¹ represents methyl or a radical of the formula —NR⁷R⁸, inwhich R⁷ and R⁸ independently of one another represent (C₁-C₄)-alkyl,which may be mono- or disubstituted by hydroxyl, or R⁷ and R⁸ togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated heterocycle which may contain a further heteroatomO or N, where N is substituted by hydrogen or (C₁-C₃)-alkyl, which forits part may be substituted by hydroxyl, R³ represents phenyl, which isoptionally substituted in the para-position by fluorine, or representspyridyl, and R⁴ represents a radical of the formula —C(O)—NR¹⁰R¹¹, inwhich R¹⁰ and R¹¹ represent hydrogen, and their salts, hydrates,hydrates of the salts and solvates.
 6. Compounds according to claim 1,characterized by one of the following stereochemical configurationsaccording to formulae (Ia) to (Id):


7. Compounds according to claim 1, characterized by the followingstereochemical configuration according to formula (Id):


8. Compounds according to claim 1 having the following structures:(1R,2R)-N-[(1S)-2-amino-1-(4-fluorophenyl)-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(4-fluorophenyl)amino]methyl}phenyl)cyclohexanecarboxamide

(1R,2R)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-(4-{[[(dimethylamino)carbonyl](phenyl)amino]methyl}phenyl)cyclohexanecarboxamide

(1R,2R)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-[4-({cyclopropyl[(dimethylamino)carbonyl]amino}methyl)phenyl]cyclohexanecarboxamide

(1R,2R)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]-2-(4-{[[(diethylamino)carbonyl](2-pyridinyl)amino]methyl}phenyl)cyclohexanecarboxamide

N-{4-[(1R,2R)-2-({[(1S)-2-amino-2-oxo-1-phenylethyl]amino}carbonyl)-cyclohexyl]benzyl}-N-phenyl-4-morpholinecarboxamide

(S)-N-{{(1R,2R)-2-(4-{[{[2-hydroxylethylamino]carbonyl}(phenyl)amino]-methyl}phenyl)cyclohex-1-yl}carbonyl}-phenylglycinamide

(1R,2R)-2-(4-{[acetyl(2-pyridinyl)amino]methyl}phenyl)-N-[(1S)-2-amino-2-oxo-1-phenylethyl]cyclohexancarboxamide

(1R,2R)-N-[(1S)-2-amino-1-phenyl-2-oxoethyl]-2-(4-{[{[ethyl(2-hydroxyethyl)amino]carbonyl}(phenyl)amino]methyl}phenyl)cyclohexanecarboxamide

4-[(1R,2R)-2-({[(1S)-2-amino-1-(4-fluorophenyl)-2-oxoethyl]amino}-carbonyl)cyclohexyl]benzyl4-(2-hydroxyethyl)-1-piperazinecarbamate

4-[(1R,2R)-2-({[(1S)-2-amino-1-phenyl-2-oxoethyl]amino}carbonyl)-cyclohexyl]benzyl-4-(2-hydroxyethyl)-1-piperazinecarbamate

and their salts, hydrates, hydrates of the salts and solvates. 9.Process for preparing compounds of the formula (I), characterized inthat [A] compounds of the formula (H)

in which D is as defined in claim 1, T represents (C₁-C₄)-alkyl, and Vrepresents a suitable leaving group are initially converted by reactionwith compounds of the formula (III) B—H  (III), in which B represents

or optionally, if R¹ reprsents OR⁹, represents

and R¹ and A are as defined in claim 1, and to the compounds of theformula (IV)

in which B and T are as defined above and D is as defined in claim 1,these compounds are in a next step converted with acids or bases intothe corresponding carboxylic acids of the formula (V)

in which R¹, A and D are as defined in claim 1, and these compounds arefinally reacted in inert solvents according to known methods withcompounds of the formula (VI) or salts thereof

in which R³ and R⁴ are as defined in claim 1, or [B] if A represents anoxygen atom or NR⁵, compounds of the formula (VII)

in which D, R³ and R⁴ are as defined in claim 1, and A represents anoxygen atom or a group of the formula N—R⁵, where R⁵ is as defined inclaim 1, are reacted either with compounds of the formula (VIII)

in which R¹ is as defined in claim 1 and W represents a suitable leavinggroup or with a phosgene equivalent and then with compounds of theformula (IX) R⁷R⁸NH  (IX), in which R⁷ and R⁸ are as defined in claim 1or with an isocyanate of the formula (X) R⁷NCO  (X), in which R⁷ is asdefined in claim
 1. 10. Process for preparing compounds of the formula(I), characterized in that [A] compounds of the formula (V)

in which R¹, A and D are as defined in claim 1, are reacted in inertsolvents according to known methods with compounds of the formula (VI)or salts thereof

in which R³ and R⁴ are as defined in claim 1, or [B] if A represents anoxygen atom or NR⁵, compounds of the formula (VII)

in which D, R³ and R⁴ are as defined in claim 1, and A represents anoxygen atom or a group of the formula N—R⁵, where R⁵ is as defined inclaim 1, are reacted either with compounds of the formula (VIII)

in which R¹ is as defined in claim 1 and W represents a suitable leavinggroup or with a phosgene equivalent and then with compounds of theformula (IX) R⁷R⁸NH  (IX), in which R⁷ and R⁸ are as defined in claim 1,or with an isocyanate of the formula (X) R⁷NCO  (X), in which R⁷ is asdefined in claim
 1. 11. Compounds of the formula (V)

in which R¹, A and D are as defined in claim 1, and their salts,hydrates, hydrates of the salts and solvates.
 12. Compounds of theformula (VII)

in which R³, R⁴, A and D are as defined in claim 1, and their salts,hydrates, hydrates of the salts and solvates.
 13. Compounds as definedin any of the preceding claims for controlling diseases. 14.Medicaments, comprising at least one compound of the formula (I) asdefined in any of the preceding claims and at least one further activecompound.
 15. Medicaments, comprising at least one compound of theformula (1) as defined in any of the preceding claims and at least onefurther auxiliary.
 16. Use of compounds of the formula (I) as defined inany of the preceding claims for preparing medicaments for the preventionand/or treatment of peripheral and cardiovascular disorders caused byischaemia.
 17. Use of compounds of the formula (I) as defined in any ofthe preceding claims for preparing medicaments for the acute and chronictreatment of ischaemic disorders of the cardiovascular system such as,for example, coronary heart disease, stable and unstable anginapectoris, of peripheral and arterial occlusive diseases, of thromboticvascular occlusions, of myocardial infarction and of reperfusion damage.